AVAHO

In metastatic breast cancer, a fixed dose of capecitabine given on a 7-day-on, 7-day-off schedule had similar efficacy and reduced adverse events compared with the standard 14-day-on, 7-day-off schedule, in a new study.

Both progression-free survival (PFS) and overall survival (OS) were similar between the two groups, but patients on the alternative schedule experienced fewer cases of hand-foot syndrome (HFS), diarrhea, and stomatitis, and also had fewer discontinuations and dose modifications.

The Food and Drug Administration–approved dose of capecitabine is 1,250 mg/m², but 14 days of treatment can lead to significant toxicity, said Qamar Khan, MD, during a presentation of the study at the annual meeting of the American Society of Clinical Oncology. “Mathematical models applied to xenograft [animal model] data suggest that the maximum cytotoxic effect of capecitabine occurs after about 7 days of treatment, beyond which time only toxicity increases,” Dr. Khan said during his talk on the randomized control trial.

The researchers randomized 153 patients to receive a fixed 1,500-mg capecitabine dose twice per day on a 7-day-on, 7-day-off schedule (7/7), or the 1,250–mg/m² dose twice per day for 14 days followed by 7 days off (14/7). The median age was 60 years, and 85.6% were White, 8.5% were African American, 3.3% were Hispanic, 0.7% were American Indian or Alaskan Native, and 2.0% were other. With respect to disease characteristics, 44% had visceral metastasis, 78% were hormone receptor positive/HER2 negative, and 11% had triple-negative breast cancer. About two-thirds (65%) had received no prior chemotherapy.

Restricted mean survival time (RMST) at 36 months for PFS was 13.9 months in the 7/7 group and 14.6 months in the 14/7 group (difference, 0.7 months; 95.5% CI, –3.14 to 4.57 months). The objective response rate was 8.9% in the 7/7 group and 19.6% in the 14/7 group (P = .11). Median OS was 19.8 months in the 7/7 group and 17.5 months in the 14/7 group (hazard ratio, 0.76; P = .17). The RMST at 47 months for OS was 24.5 months in the 7/7 group and 20.9 months in the 14/7 group (difference, –3.6 months; 95% CI, –8.89 to 1.54 months).

The researchers found no differences in subgroup analyses by visceral metastasis, breast cancer subtype, or number of lines of previous therapy.

The toxicity profile of 7/7 was better with respect to grade 2-4 diarrhea (2.5% vs. 20.5%, P = .0008), grade 2-4 HFS (3.8% vs. 15.1%; P = .0019), and grade 2-4 mucositis (0% vs. 5.5%; P =.0001).
 

Findings back up clinical practice

“The fixed-dose capecitabine dosing is something that’s been done a lot in practice, because a lot of practitioners recognize that giving the drug for two weeks in a row with a week break is overly toxic, so it’s something we’ve been doing in the community for quite a while,” said Michael Danso, MD, who comoderated the session.

Still, the safety and efficacy data back up that general clinical practice. “There was a randomized trial and colon cancer that didn’t show [equivalent outcomes with the alternate dosing schedule]. So to see that it’s safe and effective in breast cancer is an important [finding],” said Dr. Danso, who is the Research Director at Virginia Oncology Associates, Norfolk.

During the question-and-answer following the talk, Jeffrey Kirshner, MD, a medical oncologist at Hematology-Oncology Associates of Central New York, East Syracuse, noted that his practice has used a similar schedule for years. “I really commend you for doing that study. It really supports what many of us in the real world have been doing for many years. We figured this out empirically, both upfront and when patients can’t tolerate [the 14/7 schedule].”
 

Fixed dose versus body surface area

Dr. Kirshner also said his practice uses a dose of 1 g/m² of body surface area on a 7/7 schedule rather than a fixed dose as was done in Dr. Khan’s study. “If you use the higher dose, you might have seen a higher response rate because many of our patients, as you know, have a body surface [BSA] area much greater than 1.5 g/m².”

Dr. Khan responded that there is little data available on BSA dosing. “We selected 1,500 mg because a lot of people are practicing that, and for convenience, and that most patients who started at a higher dose eventually wound up on a dose of 1,500 mg twice daily.”

Dr. Kirshner also pointed out that the study was conducted in a population with metastatic disease. “I think we need to emphasize that we do not use the 7/7 regimen in a potentially curative setting, such as the CREATE-X regimen for triple-negative [breast cancer].”

Dr. Khan agreed. “I would use the same dose as the CREATE-X trial in the adjuvant setting,” he responded.

Dr. Danso has received honoraria from Amgen and has consulted or advised Immunomedics, Novartis, Pfizer, and Seagen. Dr. Khan and Dr. Kirshner have no relevant financial disclosures.

In metastatic breast cancer, a fixed dose of capecitabine given on a 7-day-on, 7-day-off schedule had similar efficacy and reduced adverse events compared with the standard 14-day-on, 7-day-off schedule, in a new study.

Both progression-free survival (PFS) and overall survival (OS) were similar between the two groups, but patients on the alternative schedule experienced fewer cases of hand-foot syndrome (HFS), diarrhea, and stomatitis, and also had fewer discontinuations and dose modifications.

The Food and Drug Administration–approved dose of capecitabine is 1,250 mg/m², but 14 days of treatment can lead to significant toxicity, said Qamar Khan, MD, during a presentation of the study at the annual meeting of the American Society of Clinical Oncology. “Mathematical models applied to xenograft [animal model] data suggest that the maximum cytotoxic effect of capecitabine occurs after about 7 days of treatment, beyond which time only toxicity increases,” Dr. Khan said during his talk on the randomized control trial.

The researchers randomized 153 patients to receive a fixed 1,500-mg capecitabine dose twice per day on a 7-day-on, 7-day-off schedule (7/7), or the 1,250–mg/m² dose twice per day for 14 days followed by 7 days off (14/7). The median age was 60 years, and 85.6% were White, 8.5% were African American, 3.3% were Hispanic, 0.7% were American Indian or Alaskan Native, and 2.0% were other. With respect to disease characteristics, 44% had visceral metastasis, 78% were hormone receptor positive/HER2 negative, and 11% had triple-negative breast cancer. About two-thirds (65%) had received no prior chemotherapy.

Restricted mean survival time (RMST) at 36 months for PFS was 13.9 months in the 7/7 group and 14.6 months in the 14/7 group (difference, 0.7 months; 95.5% CI, –3.14 to 4.57 months). The objective response rate was 8.9% in the 7/7 group and 19.6% in the 14/7 group (P = .11). Median OS was 19.8 months in the 7/7 group and 17.5 months in the 14/7 group (hazard ratio, 0.76; P = .17). The RMST at 47 months for OS was 24.5 months in the 7/7 group and 20.9 months in the 14/7 group (difference, –3.6 months; 95% CI, –8.89 to 1.54 months).

The researchers found no differences in subgroup analyses by visceral metastasis, breast cancer subtype, or number of lines of previous therapy.

The toxicity profile of 7/7 was better with respect to grade 2-4 diarrhea (2.5% vs. 20.5%, P = .0008), grade 2-4 HFS (3.8% vs. 15.1%; P = .0019), and grade 2-4 mucositis (0% vs. 5.5%; P =.0001).
 

Findings back up clinical practice

“The fixed-dose capecitabine dosing is something that’s been done a lot in practice, because a lot of practitioners recognize that giving the drug for two weeks in a row with a week break is overly toxic, so it’s something we’ve been doing in the community for quite a while,” said Michael Danso, MD, who comoderated the session.

Still, the safety and efficacy data back up that general clinical practice. “There was a randomized trial and colon cancer that didn’t show [equivalent outcomes with the alternate dosing schedule]. So to see that it’s safe and effective in breast cancer is an important [finding],” said Dr. Danso, who is the Research Director at Virginia Oncology Associates, Norfolk.

During the question-and-answer following the talk, Jeffrey Kirshner, MD, a medical oncologist at Hematology-Oncology Associates of Central New York, East Syracuse, noted that his practice has used a similar schedule for years. “I really commend you for doing that study. It really supports what many of us in the real world have been doing for many years. We figured this out empirically, both upfront and when patients can’t tolerate [the 14/7 schedule].”
 

Fixed dose versus body surface area

Dr. Kirshner also said his practice uses a dose of 1 g/m² of body surface area on a 7/7 schedule rather than a fixed dose as was done in Dr. Khan’s study. “If you use the higher dose, you might have seen a higher response rate because many of our patients, as you know, have a body surface [BSA] area much greater than 1.5 g/m².”

Dr. Khan responded that there is little data available on BSA dosing. “We selected 1,500 mg because a lot of people are practicing that, and for convenience, and that most patients who started at a higher dose eventually wound up on a dose of 1,500 mg twice daily.”

Dr. Kirshner also pointed out that the study was conducted in a population with metastatic disease. “I think we need to emphasize that we do not use the 7/7 regimen in a potentially curative setting, such as the CREATE-X regimen for triple-negative [breast cancer].”

Dr. Khan agreed. “I would use the same dose as the CREATE-X trial in the adjuvant setting,” he responded.

Dr. Danso has received honoraria from Amgen and has consulted or advised Immunomedics, Novartis, Pfizer, and Seagen. Dr. Khan and Dr. Kirshner have no relevant financial disclosures.

In metastatic breast cancer, a fixed dose of capecitabine given on a 7-day-on, 7-day-off schedule had similar efficacy and reduced adverse events compared with the standard 14-day-on, 7-day-off schedule, in a new study.

Both progression-free survival (PFS) and overall survival (OS) were similar between the two groups, but patients on the alternative schedule experienced fewer cases of hand-foot syndrome (HFS), diarrhea, and stomatitis, and also had fewer discontinuations and dose modifications.

The Food and Drug Administration–approved dose of capecitabine is 1,250 mg/m², but 14 days of treatment can lead to significant toxicity, said Qamar Khan, MD, during a presentation of the study at the annual meeting of the American Society of Clinical Oncology. “Mathematical models applied to xenograft [animal model] data suggest that the maximum cytotoxic effect of capecitabine occurs after about 7 days of treatment, beyond which time only toxicity increases,” Dr. Khan said during his talk on the randomized control trial.

The researchers randomized 153 patients to receive a fixed 1,500-mg capecitabine dose twice per day on a 7-day-on, 7-day-off schedule (7/7), or the 1,250–mg/m² dose twice per day for 14 days followed by 7 days off (14/7). The median age was 60 years, and 85.6% were White, 8.5% were African American, 3.3% were Hispanic, 0.7% were American Indian or Alaskan Native, and 2.0% were other. With respect to disease characteristics, 44% had visceral metastasis, 78% were hormone receptor positive/HER2 negative, and 11% had triple-negative breast cancer. About two-thirds (65%) had received no prior chemotherapy.

Restricted mean survival time (RMST) at 36 months for PFS was 13.9 months in the 7/7 group and 14.6 months in the 14/7 group (difference, 0.7 months; 95.5% CI, –3.14 to 4.57 months). The objective response rate was 8.9% in the 7/7 group and 19.6% in the 14/7 group (P = .11). Median OS was 19.8 months in the 7/7 group and 17.5 months in the 14/7 group (hazard ratio, 0.76; P = .17). The RMST at 47 months for OS was 24.5 months in the 7/7 group and 20.9 months in the 14/7 group (difference, –3.6 months; 95% CI, –8.89 to 1.54 months).

The researchers found no differences in subgroup analyses by visceral metastasis, breast cancer subtype, or number of lines of previous therapy.

The toxicity profile of 7/7 was better with respect to grade 2-4 diarrhea (2.5% vs. 20.5%, P = .0008), grade 2-4 HFS (3.8% vs. 15.1%; P = .0019), and grade 2-4 mucositis (0% vs. 5.5%; P =.0001).
 

Findings back up clinical practice

“The fixed-dose capecitabine dosing is something that’s been done a lot in practice, because a lot of practitioners recognize that giving the drug for two weeks in a row with a week break is overly toxic, so it’s something we’ve been doing in the community for quite a while,” said Michael Danso, MD, who comoderated the session.

Still, the safety and efficacy data back up that general clinical practice. “There was a randomized trial and colon cancer that didn’t show [equivalent outcomes with the alternate dosing schedule]. So to see that it’s safe and effective in breast cancer is an important [finding],” said Dr. Danso, who is the Research Director at Virginia Oncology Associates, Norfolk.

During the question-and-answer following the talk, Jeffrey Kirshner, MD, a medical oncologist at Hematology-Oncology Associates of Central New York, East Syracuse, noted that his practice has used a similar schedule for years. “I really commend you for doing that study. It really supports what many of us in the real world have been doing for many years. We figured this out empirically, both upfront and when patients can’t tolerate [the 14/7 schedule].”
 

Fixed dose versus body surface area

Dr. Kirshner also said his practice uses a dose of 1 g/m² of body surface area on a 7/7 schedule rather than a fixed dose as was done in Dr. Khan’s study. “If you use the higher dose, you might have seen a higher response rate because many of our patients, as you know, have a body surface [BSA] area much greater than 1.5 g/m².”

Dr. Khan responded that there is little data available on BSA dosing. “We selected 1,500 mg because a lot of people are practicing that, and for convenience, and that most patients who started at a higher dose eventually wound up on a dose of 1,500 mg twice daily.”

Dr. Kirshner also pointed out that the study was conducted in a population with metastatic disease. “I think we need to emphasize that we do not use the 7/7 regimen in a potentially curative setting, such as the CREATE-X regimen for triple-negative [breast cancer].”

Dr. Khan agreed. “I would use the same dose as the CREATE-X trial in the adjuvant setting,” he responded.

Dr. Danso has received honoraria from Amgen and has consulted or advised Immunomedics, Novartis, Pfizer, and Seagen. Dr. Khan and Dr. Kirshner have no relevant financial disclosures.

Triple-negative breast cancer (TNBC) is characterized by the absence of hormonal receptors and human epidermal growth factor receptor 2 (HER2) expression. Historically, treatments targeting HER2 were found to be ineffective in patients with TNBC and known HER2-zero status. Researchers more recently identified a new type of TNBC involving patients with low expression of HER2. Patients with this type of breast cancer, now referred to as HER2-low, have immunohistochemical (IHC) analysis scores of 1+ or 2+ and negative in situ hybridization (ISH) stain.

In a new study, patients with TNBC who initially tested as having HER2-zero status were later found to have HER2-low status following repeated biopsies. These HER2-low results were of great clinical significance for this patient population, said Yael Bar, MD, PhD, during her presentation of the research, at the annual meeting of the American Society of Clinical Oncology (ASCO).

Previously, the DESTINY-Breast04 trial demonstrated that the antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) improved progression-free survival (PFS) and overall survival (OS) for patients with HER2-low metastatic breast cancer. “As a result [of the DESTINY-Breast04 findings], T-DXd is now approved for HER2-low but not HER2-zero triple-negative metastatic breast cancer."

“While HER2-low is detected in about 30%-50% of patients with triple-negative breast cancer, several studies have shown that HER2 status is heterogeneous and also dynamic over time, said Dr. Bar, who is an international research fellow in the breast cancer group at Mass General Cancer Center, Boston.

In the new study, Dr. Bar and her co-authors retrospectively identified 512 TNBC patients from 2000 to 2022 from an institutional database. They included core, surgical, or metastatic biopsies. Participants had a mean age of 52 years, with 54% over age 50. They were 83% White, 7% African American, 5% Asian, 3% Hispanic, and 2% other. Stage II was most common at diagnosis at 48%, followed by stage 1 (28%), stage 3 (14%), and stage IV (8%).

Most patients had undergone one (38%) or two (45%) biopsies, while 9% underwent three biopsies, 6% underwent four biopsies, and 2% underwent five or more.

Among all 512 patients in the study, 60% had a HER2-low result on their first biopsy. As of the second biopsy, 73% had at least one HER2-low result, with 13% of the first HER2-low results occurring at the second biopsy. As of the third biopsy, 81% had a HER2-low result, with 9% occurring for the first time. At the fourth biopsy, 86% had a positive result, with 8% occurring for the first time. All patients with five or more biopsies had at least one HER2-low result and none were first-time results.

At the second biopsy, a HER2-low result was detected for 32% of patients for the first time. At the third biopsy, a new HER2-low result was detected in 33%, and at the fourth biopsy, a new HER-2 result was detected in 38%.

The researchers matched early and metastatic biopsies in 71 patients, and 44% had changed status: 68% of those with a status change went HER2-low to HER2-zero, 26% from HER2-zero to HER2-low, and 6% from HER2-low to HER2-positive. Among 50 patients with matched metastatic biopsies, 33% had a change in status, with 63% going from HER2-zero to HER2-low, 31% from HER2-low to HER2-zero, and 6% from HER2-low to HER2-positive.

“We showed here that repeat biopsies can identify new HER2-low results for patients who were previously ineligible for T-DXd; and therefore, we think that a repeat biopsy could be considered if feasible and safe. Also, if a repeat biopsy is performed for any reason, but mainly upon metastatic recurrence, receptors should be retested,” said Dr. Bar.

After Dr. Bar’s presentation, Barbara Pistilli, MD served as a discussant. She noted the increased HER2-low results over successive biopsies. “However, here the question is, are these results related to the changes in the analytical methods over the past 20 years or the changes in the guidelines in terms of definition of HER2 status, or are they more related to a true evolution of HER2 status with the evolution of the disease?” she said during her presentation. Dr. Pistilli is chair of the breast disease committee at Gustave Roussy in Villejuif, France.

She also said that HER2 expression can vary even between different parts of the same tumor and called for alternative methods to following HER2 expression. “I don’t think that we can follow our patients with multiple biopsies over the disease evolution, so we have to find other tools, such as target-positive [circulating tumor cells], or antibody-radiolabeled PET scan in order to better follow the intermetastasis target heterogeneity over time, and finally define what is the optimal ADC sequential strategy for each patient,” said Dr. Pistilli.

Comoderator Michael Danso, MD, also weighed in when asked for comment. 

“It was an important trial to show that serial biopsies potentially allow more patients to receive trastuzumab deruxtecan,” said Dr. Danso, who is the research director at Virginia Oncology Associates, Norfolk. However, he pointed out the concerns of a statistician who had spoken up during the question-and-answer session who said that the positive results could simply be the consequence of repeated testing. “If you do a test often enough, statistically you’re going to get a difference in outcome. That was an important point made. Also, if you’re going to get 100% of patients who are eventually going to [develop HER2-low status], the question is, can you just treat everybody with trastuzumab deruxtecan and not do these sequential biopsies? Obviously that is subject to cost; it’s subject to toxicity as well, so you probably want documentation that there is a HER2-low result,” said Dr. Danso.

Dr. Bar has no relevant financial disclosures. Dr. Pistilli has consulted for or advised AstraZeneca, Daiichi Sankyo/UCB Japan, Myriad Genetics, Novartis, PIERRE FABRE, and Puma Biotechnology. She has received research funding through her institution from AstraZeneca, Daiichi Sankyo, Gilead Sciences, Merus, Pfizer, and Puma Biotechnology. She has received travel or accommodation expenses from AstraZeneca, Daiichi Sankyo Europe, MSD Oncology, Novartis, Pfizer, and Pierre Fabre. Dr. Danso has received honoraria from Amgen and has consulted or advised Immunomedics, Novartis, Pfizer, and Seagen.

*This story was updated on 6/13/2023.

Triple-negative breast cancer (TNBC) is characterized by the absence of hormonal receptors and human epidermal growth factor receptor 2 (HER2) expression. Historically, treatments targeting HER2 were found to be ineffective in patients with TNBC and known HER2-zero status. Researchers more recently identified a new type of TNBC involving patients with low expression of HER2. Patients with this type of breast cancer, now referred to as HER2-low, have immunohistochemical (IHC) analysis scores of 1+ or 2+ and negative in situ hybridization (ISH) stain.

In a new study, patients with TNBC who initially tested as having HER2-zero status were later found to have HER2-low status following repeated biopsies. These HER2-low results were of great clinical significance for this patient population, said Yael Bar, MD, PhD, during her presentation of the research, at the annual meeting of the American Society of Clinical Oncology (ASCO).

Previously, the DESTINY-Breast04 trial demonstrated that the antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) improved progression-free survival (PFS) and overall survival (OS) for patients with HER2-low metastatic breast cancer. “As a result [of the DESTINY-Breast04 findings], T-DXd is now approved for HER2-low but not HER2-zero triple-negative metastatic breast cancer."

“While HER2-low is detected in about 30%-50% of patients with triple-negative breast cancer, several studies have shown that HER2 status is heterogeneous and also dynamic over time, said Dr. Bar, who is an international research fellow in the breast cancer group at Mass General Cancer Center, Boston.

In the new study, Dr. Bar and her co-authors retrospectively identified 512 TNBC patients from 2000 to 2022 from an institutional database. They included core, surgical, or metastatic biopsies. Participants had a mean age of 52 years, with 54% over age 50. They were 83% White, 7% African American, 5% Asian, 3% Hispanic, and 2% other. Stage II was most common at diagnosis at 48%, followed by stage 1 (28%), stage 3 (14%), and stage IV (8%).

Most patients had undergone one (38%) or two (45%) biopsies, while 9% underwent three biopsies, 6% underwent four biopsies, and 2% underwent five or more.

Among all 512 patients in the study, 60% had a HER2-low result on their first biopsy. As of the second biopsy, 73% had at least one HER2-low result, with 13% of the first HER2-low results occurring at the second biopsy. As of the third biopsy, 81% had a HER2-low result, with 9% occurring for the first time. At the fourth biopsy, 86% had a positive result, with 8% occurring for the first time. All patients with five or more biopsies had at least one HER2-low result and none were first-time results.

At the second biopsy, a HER2-low result was detected for 32% of patients for the first time. At the third biopsy, a new HER2-low result was detected in 33%, and at the fourth biopsy, a new HER-2 result was detected in 38%.

The researchers matched early and metastatic biopsies in 71 patients, and 44% had changed status: 68% of those with a status change went HER2-low to HER2-zero, 26% from HER2-zero to HER2-low, and 6% from HER2-low to HER2-positive. Among 50 patients with matched metastatic biopsies, 33% had a change in status, with 63% going from HER2-zero to HER2-low, 31% from HER2-low to HER2-zero, and 6% from HER2-low to HER2-positive.

“We showed here that repeat biopsies can identify new HER2-low results for patients who were previously ineligible for T-DXd; and therefore, we think that a repeat biopsy could be considered if feasible and safe. Also, if a repeat biopsy is performed for any reason, but mainly upon metastatic recurrence, receptors should be retested,” said Dr. Bar.

After Dr. Bar’s presentation, Barbara Pistilli, MD served as a discussant. She noted the increased HER2-low results over successive biopsies. “However, here the question is, are these results related to the changes in the analytical methods over the past 20 years or the changes in the guidelines in terms of definition of HER2 status, or are they more related to a true evolution of HER2 status with the evolution of the disease?” she said during her presentation. Dr. Pistilli is chair of the breast disease committee at Gustave Roussy in Villejuif, France.

She also said that HER2 expression can vary even between different parts of the same tumor and called for alternative methods to following HER2 expression. “I don’t think that we can follow our patients with multiple biopsies over the disease evolution, so we have to find other tools, such as target-positive [circulating tumor cells], or antibody-radiolabeled PET scan in order to better follow the intermetastasis target heterogeneity over time, and finally define what is the optimal ADC sequential strategy for each patient,” said Dr. Pistilli.

Comoderator Michael Danso, MD, also weighed in when asked for comment. 

“It was an important trial to show that serial biopsies potentially allow more patients to receive trastuzumab deruxtecan,” said Dr. Danso, who is the research director at Virginia Oncology Associates, Norfolk. However, he pointed out the concerns of a statistician who had spoken up during the question-and-answer session who said that the positive results could simply be the consequence of repeated testing. “If you do a test often enough, statistically you’re going to get a difference in outcome. That was an important point made. Also, if you’re going to get 100% of patients who are eventually going to [develop HER2-low status], the question is, can you just treat everybody with trastuzumab deruxtecan and not do these sequential biopsies? Obviously that is subject to cost; it’s subject to toxicity as well, so you probably want documentation that there is a HER2-low result,” said Dr. Danso.

Dr. Bar has no relevant financial disclosures. Dr. Pistilli has consulted for or advised AstraZeneca, Daiichi Sankyo/UCB Japan, Myriad Genetics, Novartis, PIERRE FABRE, and Puma Biotechnology. She has received research funding through her institution from AstraZeneca, Daiichi Sankyo, Gilead Sciences, Merus, Pfizer, and Puma Biotechnology. She has received travel or accommodation expenses from AstraZeneca, Daiichi Sankyo Europe, MSD Oncology, Novartis, Pfizer, and Pierre Fabre. Dr. Danso has received honoraria from Amgen and has consulted or advised Immunomedics, Novartis, Pfizer, and Seagen.

*This story was updated on 6/13/2023.

Triple-negative breast cancer (TNBC) is characterized by the absence of hormonal receptors and human epidermal growth factor receptor 2 (HER2) expression. Historically, treatments targeting HER2 were found to be ineffective in patients with TNBC and known HER2-zero status. Researchers more recently identified a new type of TNBC involving patients with low expression of HER2. Patients with this type of breast cancer, now referred to as HER2-low, have immunohistochemical (IHC) analysis scores of 1+ or 2+ and negative in situ hybridization (ISH) stain.

In a new study, patients with TNBC who initially tested as having HER2-zero status were later found to have HER2-low status following repeated biopsies. These HER2-low results were of great clinical significance for this patient population, said Yael Bar, MD, PhD, during her presentation of the research, at the annual meeting of the American Society of Clinical Oncology (ASCO).

Previously, the DESTINY-Breast04 trial demonstrated that the antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) improved progression-free survival (PFS) and overall survival (OS) for patients with HER2-low metastatic breast cancer. “As a result [of the DESTINY-Breast04 findings], T-DXd is now approved for HER2-low but not HER2-zero triple-negative metastatic breast cancer."

“While HER2-low is detected in about 30%-50% of patients with triple-negative breast cancer, several studies have shown that HER2 status is heterogeneous and also dynamic over time, said Dr. Bar, who is an international research fellow in the breast cancer group at Mass General Cancer Center, Boston.

In the new study, Dr. Bar and her co-authors retrospectively identified 512 TNBC patients from 2000 to 2022 from an institutional database. They included core, surgical, or metastatic biopsies. Participants had a mean age of 52 years, with 54% over age 50. They were 83% White, 7% African American, 5% Asian, 3% Hispanic, and 2% other. Stage II was most common at diagnosis at 48%, followed by stage 1 (28%), stage 3 (14%), and stage IV (8%).

Most patients had undergone one (38%) or two (45%) biopsies, while 9% underwent three biopsies, 6% underwent four biopsies, and 2% underwent five or more.

Among all 512 patients in the study, 60% had a HER2-low result on their first biopsy. As of the second biopsy, 73% had at least one HER2-low result, with 13% of the first HER2-low results occurring at the second biopsy. As of the third biopsy, 81% had a HER2-low result, with 9% occurring for the first time. At the fourth biopsy, 86% had a positive result, with 8% occurring for the first time. All patients with five or more biopsies had at least one HER2-low result and none were first-time results.

At the second biopsy, a HER2-low result was detected for 32% of patients for the first time. At the third biopsy, a new HER2-low result was detected in 33%, and at the fourth biopsy, a new HER-2 result was detected in 38%.

The researchers matched early and metastatic biopsies in 71 patients, and 44% had changed status: 68% of those with a status change went HER2-low to HER2-zero, 26% from HER2-zero to HER2-low, and 6% from HER2-low to HER2-positive. Among 50 patients with matched metastatic biopsies, 33% had a change in status, with 63% going from HER2-zero to HER2-low, 31% from HER2-low to HER2-zero, and 6% from HER2-low to HER2-positive.

“We showed here that repeat biopsies can identify new HER2-low results for patients who were previously ineligible for T-DXd; and therefore, we think that a repeat biopsy could be considered if feasible and safe. Also, if a repeat biopsy is performed for any reason, but mainly upon metastatic recurrence, receptors should be retested,” said Dr. Bar.

After Dr. Bar’s presentation, Barbara Pistilli, MD served as a discussant. She noted the increased HER2-low results over successive biopsies. “However, here the question is, are these results related to the changes in the analytical methods over the past 20 years or the changes in the guidelines in terms of definition of HER2 status, or are they more related to a true evolution of HER2 status with the evolution of the disease?” she said during her presentation. Dr. Pistilli is chair of the breast disease committee at Gustave Roussy in Villejuif, France.

She also said that HER2 expression can vary even between different parts of the same tumor and called for alternative methods to following HER2 expression. “I don’t think that we can follow our patients with multiple biopsies over the disease evolution, so we have to find other tools, such as target-positive [circulating tumor cells], or antibody-radiolabeled PET scan in order to better follow the intermetastasis target heterogeneity over time, and finally define what is the optimal ADC sequential strategy for each patient,” said Dr. Pistilli.

Comoderator Michael Danso, MD, also weighed in when asked for comment. 

“It was an important trial to show that serial biopsies potentially allow more patients to receive trastuzumab deruxtecan,” said Dr. Danso, who is the research director at Virginia Oncology Associates, Norfolk. However, he pointed out the concerns of a statistician who had spoken up during the question-and-answer session who said that the positive results could simply be the consequence of repeated testing. “If you do a test often enough, statistically you’re going to get a difference in outcome. That was an important point made. Also, if you’re going to get 100% of patients who are eventually going to [develop HER2-low status], the question is, can you just treat everybody with trastuzumab deruxtecan and not do these sequential biopsies? Obviously that is subject to cost; it’s subject to toxicity as well, so you probably want documentation that there is a HER2-low result,” said Dr. Danso.

Dr. Bar has no relevant financial disclosures. Dr. Pistilli has consulted for or advised AstraZeneca, Daiichi Sankyo/UCB Japan, Myriad Genetics, Novartis, PIERRE FABRE, and Puma Biotechnology. She has received research funding through her institution from AstraZeneca, Daiichi Sankyo, Gilead Sciences, Merus, Pfizer, and Puma Biotechnology. She has received travel or accommodation expenses from AstraZeneca, Daiichi Sankyo Europe, MSD Oncology, Novartis, Pfizer, and Pierre Fabre. Dr. Danso has received honoraria from Amgen and has consulted or advised Immunomedics, Novartis, Pfizer, and Seagen.

*This story was updated on 6/13/2023.

CHICAGO – Nearly 60% of health care providers surveyed failed to choose the same treatment strategies for HER2– early breast cancer as a panel of five oncologists with expertise in breast cancer, a new study finds.

The discrepancy suggests that many providers aren’t aware of the findings of recent landmark trials that formed the basis of the panel’s opinions, said study coauthor Denise A. Yardley, MD, of Tennessee Oncology and Sarah Cannon Research Institute in Nashville, in an interview. The findings, based on responses to a treatment decision tool, were presented in a poster at the annual meeting of the American Society of Clinical Oncology.

Study methods and results

For the new study, researchers analyzed how 547 providers – and the panel – responded to 10 case scenarios in high-risk HER2– early breast cancer between June 2022 and January 2023.

Among the providers surveyed, 72% identified as physicians, including oncologists, hematologists/oncologists, surgery oncologists, radiation oncologists, and pathologists. One percent said they were nurse practitioners or physician assistants, 7% said they were pharmacists, 1% were nurses, and the specific roles of the remaining 19% were unknown, but included medical students, according to Dr. Yardley, who is a breast cancer oncologist.

The study authors developed the free decision tool – available via the medical education company Clinical Care Options – to help oncologists navigate new treatment options for high-risk HER2– early breast cancer. The Food and Drug Administration has recently approved drugs such as abemaciclib, olaparib, and pembrolizumab for the condition.

Health care providers enter details into the tool about their patients along with their intended treatment plans. The tool then shows them recommendations for treatment from a panel of five oncologists with expertise in oncology. The members of the panel based their perspectives on the findings of the KEYNOTE-522 (pembrolizumab), OlympiA (olaparib), and monarchE (abemaciclib) trials.

The oncologists with expertise in breast cancer, who provided recommendations in March 2022, generally agreed about the best treatments, Dr. Yardley said.

The other health care providers surveyed didn’t agree with the breast cancer experts about the best treatment 58.8% of the time.

For example, one scenario describes a HR+, HER2– patient with no deleterious BRCA mutation – or unknown status – who fits the monarchE high-risk criteria. All the breast cancer experts on the panel recommended abemaciclib and endocrine therapy. But 203 providers supported a variety of strategies: endocrine therapy alone (9%), chemotherapy followed by endocrine therapy (49%), and olaparib and endocrine therapy (2%). Only 37% opted for abemaciclib and endocrine therapy, and 4% were uncertain.

Another scenario describes a patient with triple-negative breast cancer with no residual disease after neoadjuvant chemotherapy. All the experts agreed on a strategy of no adjuvant therapy plus observation. Forty percent of 25 providers agreed with this approach, but 24% were uncertain, 12% chose pembrolizumab, and 24% chose capecitabine.

In many cases, providers chose more intensive treatment options than the experts did, Dr. Yardley said.

Overtreatment in cancer is often a reflex for oncologists, she said, although “we’re learning to deescalate these treatment algorithms where there is really no benefit [to extra treatment].”

“It’s a challenge for some of these oncologists who are busy and dealing with multiple solid tumor types to keep up with the nuances of a rapidly changing field,” Dr. Yardley noted.

Many community oncologists aren’t specialists in one type of cancer and must try to keep up with treatment recommendations regarding multiple types, she continued.
 

Decision tool’s value explained

According to the study, 32% of providers changed their treatment choices in clinical practice after they learned about the expert perspectives via the decision tool; 46% said the expert opinions confirmed that their choices were best practice.

The value of the tool is its ability to help providers make better decisions about patient care, Dr. Yardley said. “There seems to be a need for this kind of support.”

In an interview, University of Pittsburgh Medical Center oncologist Adam M. Brufsky, MD, PhD – who wasn’t involved with the study – said he was surprised by the amount of disagreement between the expert and provider perspectives on treatment. However, he noted that community oncologists – unlike the breast cancer experts – often don’t see just one type of cancer.

“You just have to know so much now as an oncologist,” Dr. Brufsky said. He recommended that colleagues take advantage of decision support tools, such as cancer treatment pathways.

The study was funded by AstraZeneca, Lilly, and Merck Sharp & Dohme. Dr. Yardley has no disclosures, and disclosure information from other authors was not available. Dr. Brufsky discloses consulting support from AstraZeneca, Lilly, and Merck and grants from AstraZeneca.

CHICAGO – Nearly 60% of health care providers surveyed failed to choose the same treatment strategies for HER2– early breast cancer as a panel of five oncologists with expertise in breast cancer, a new study finds.

The discrepancy suggests that many providers aren’t aware of the findings of recent landmark trials that formed the basis of the panel’s opinions, said study coauthor Denise A. Yardley, MD, of Tennessee Oncology and Sarah Cannon Research Institute in Nashville, in an interview. The findings, based on responses to a treatment decision tool, were presented in a poster at the annual meeting of the American Society of Clinical Oncology.

Study methods and results

For the new study, researchers analyzed how 547 providers – and the panel – responded to 10 case scenarios in high-risk HER2– early breast cancer between June 2022 and January 2023.

Among the providers surveyed, 72% identified as physicians, including oncologists, hematologists/oncologists, surgery oncologists, radiation oncologists, and pathologists. One percent said they were nurse practitioners or physician assistants, 7% said they were pharmacists, 1% were nurses, and the specific roles of the remaining 19% were unknown, but included medical students, according to Dr. Yardley, who is a breast cancer oncologist.

The study authors developed the free decision tool – available via the medical education company Clinical Care Options – to help oncologists navigate new treatment options for high-risk HER2– early breast cancer. The Food and Drug Administration has recently approved drugs such as abemaciclib, olaparib, and pembrolizumab for the condition.

Health care providers enter details into the tool about their patients along with their intended treatment plans. The tool then shows them recommendations for treatment from a panel of five oncologists with expertise in oncology. The members of the panel based their perspectives on the findings of the KEYNOTE-522 (pembrolizumab), OlympiA (olaparib), and monarchE (abemaciclib) trials.

The oncologists with expertise in breast cancer, who provided recommendations in March 2022, generally agreed about the best treatments, Dr. Yardley said.

The other health care providers surveyed didn’t agree with the breast cancer experts about the best treatment 58.8% of the time.

For example, one scenario describes a HR+, HER2– patient with no deleterious BRCA mutation – or unknown status – who fits the monarchE high-risk criteria. All the breast cancer experts on the panel recommended abemaciclib and endocrine therapy. But 203 providers supported a variety of strategies: endocrine therapy alone (9%), chemotherapy followed by endocrine therapy (49%), and olaparib and endocrine therapy (2%). Only 37% opted for abemaciclib and endocrine therapy, and 4% were uncertain.

Another scenario describes a patient with triple-negative breast cancer with no residual disease after neoadjuvant chemotherapy. All the experts agreed on a strategy of no adjuvant therapy plus observation. Forty percent of 25 providers agreed with this approach, but 24% were uncertain, 12% chose pembrolizumab, and 24% chose capecitabine.

In many cases, providers chose more intensive treatment options than the experts did, Dr. Yardley said.

Overtreatment in cancer is often a reflex for oncologists, she said, although “we’re learning to deescalate these treatment algorithms where there is really no benefit [to extra treatment].”

“It’s a challenge for some of these oncologists who are busy and dealing with multiple solid tumor types to keep up with the nuances of a rapidly changing field,” Dr. Yardley noted.

Many community oncologists aren’t specialists in one type of cancer and must try to keep up with treatment recommendations regarding multiple types, she continued.
 

Decision tool’s value explained

According to the study, 32% of providers changed their treatment choices in clinical practice after they learned about the expert perspectives via the decision tool; 46% said the expert opinions confirmed that their choices were best practice.

The value of the tool is its ability to help providers make better decisions about patient care, Dr. Yardley said. “There seems to be a need for this kind of support.”

In an interview, University of Pittsburgh Medical Center oncologist Adam M. Brufsky, MD, PhD – who wasn’t involved with the study – said he was surprised by the amount of disagreement between the expert and provider perspectives on treatment. However, he noted that community oncologists – unlike the breast cancer experts – often don’t see just one type of cancer.

“You just have to know so much now as an oncologist,” Dr. Brufsky said. He recommended that colleagues take advantage of decision support tools, such as cancer treatment pathways.

The study was funded by AstraZeneca, Lilly, and Merck Sharp & Dohme. Dr. Yardley has no disclosures, and disclosure information from other authors was not available. Dr. Brufsky discloses consulting support from AstraZeneca, Lilly, and Merck and grants from AstraZeneca.

CHICAGO – Nearly 60% of health care providers surveyed failed to choose the same treatment strategies for HER2– early breast cancer as a panel of five oncologists with expertise in breast cancer, a new study finds.

The discrepancy suggests that many providers aren’t aware of the findings of recent landmark trials that formed the basis of the panel’s opinions, said study coauthor Denise A. Yardley, MD, of Tennessee Oncology and Sarah Cannon Research Institute in Nashville, in an interview. The findings, based on responses to a treatment decision tool, were presented in a poster at the annual meeting of the American Society of Clinical Oncology.

Study methods and results

For the new study, researchers analyzed how 547 providers – and the panel – responded to 10 case scenarios in high-risk HER2– early breast cancer between June 2022 and January 2023.

Among the providers surveyed, 72% identified as physicians, including oncologists, hematologists/oncologists, surgery oncologists, radiation oncologists, and pathologists. One percent said they were nurse practitioners or physician assistants, 7% said they were pharmacists, 1% were nurses, and the specific roles of the remaining 19% were unknown, but included medical students, according to Dr. Yardley, who is a breast cancer oncologist.

The study authors developed the free decision tool – available via the medical education company Clinical Care Options – to help oncologists navigate new treatment options for high-risk HER2– early breast cancer. The Food and Drug Administration has recently approved drugs such as abemaciclib, olaparib, and pembrolizumab for the condition.

Health care providers enter details into the tool about their patients along with their intended treatment plans. The tool then shows them recommendations for treatment from a panel of five oncologists with expertise in oncology. The members of the panel based their perspectives on the findings of the KEYNOTE-522 (pembrolizumab), OlympiA (olaparib), and monarchE (abemaciclib) trials.

The oncologists with expertise in breast cancer, who provided recommendations in March 2022, generally agreed about the best treatments, Dr. Yardley said.

The other health care providers surveyed didn’t agree with the breast cancer experts about the best treatment 58.8% of the time.

For example, one scenario describes a HR+, HER2– patient with no deleterious BRCA mutation – or unknown status – who fits the monarchE high-risk criteria. All the breast cancer experts on the panel recommended abemaciclib and endocrine therapy. But 203 providers supported a variety of strategies: endocrine therapy alone (9%), chemotherapy followed by endocrine therapy (49%), and olaparib and endocrine therapy (2%). Only 37% opted for abemaciclib and endocrine therapy, and 4% were uncertain.

Another scenario describes a patient with triple-negative breast cancer with no residual disease after neoadjuvant chemotherapy. All the experts agreed on a strategy of no adjuvant therapy plus observation. Forty percent of 25 providers agreed with this approach, but 24% were uncertain, 12% chose pembrolizumab, and 24% chose capecitabine.

In many cases, providers chose more intensive treatment options than the experts did, Dr. Yardley said.

Overtreatment in cancer is often a reflex for oncologists, she said, although “we’re learning to deescalate these treatment algorithms where there is really no benefit [to extra treatment].”

“It’s a challenge for some of these oncologists who are busy and dealing with multiple solid tumor types to keep up with the nuances of a rapidly changing field,” Dr. Yardley noted.

Many community oncologists aren’t specialists in one type of cancer and must try to keep up with treatment recommendations regarding multiple types, she continued.
 

Decision tool’s value explained

According to the study, 32% of providers changed their treatment choices in clinical practice after they learned about the expert perspectives via the decision tool; 46% said the expert opinions confirmed that their choices were best practice.

The value of the tool is its ability to help providers make better decisions about patient care, Dr. Yardley said. “There seems to be a need for this kind of support.”

In an interview, University of Pittsburgh Medical Center oncologist Adam M. Brufsky, MD, PhD – who wasn’t involved with the study – said he was surprised by the amount of disagreement between the expert and provider perspectives on treatment. However, he noted that community oncologists – unlike the breast cancer experts – often don’t see just one type of cancer.

“You just have to know so much now as an oncologist,” Dr. Brufsky said. He recommended that colleagues take advantage of decision support tools, such as cancer treatment pathways.

The study was funded by AstraZeneca, Lilly, and Merck Sharp & Dohme. Dr. Yardley has no disclosures, and disclosure information from other authors was not available. Dr. Brufsky discloses consulting support from AstraZeneca, Lilly, and Merck and grants from AstraZeneca.

Patients with acute promyelocytic leukemia (APL) – previously considered among the most rapidly fatal forms of acute myeloid leukemia (AML) – now show survival rates exceeding 90% at 10 years after treatment with a chemotherapy-free regimen of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), with a survival advantage over ATRA plus chemotherapy in low- and intermediate-risk patients.

“In a large cohort of patients with APL, the chemo-free combination of ATRA/ATO is confirmed as the best treatment option, prolonging overall and event-free survival and reducing the relapse rate compared with ATRA/chemotherapy,” said first author Maria Teresa Voso, MD, of Tor Vergata University, in Rome, in presenting the findings at the 2023 annual meeting of the European Hematology Association.

APL, though rare, makes up about 10% of new AML cases, and the advent of the chemo-free ATRA-ATO regimen in recent years has transformed the disease, significantly improving survival.

However, with ongoing questions regarding factors associated with treatment benefits based on issues including the level of risk, Dr. Voso and colleagues turned to data from the large European Union–funded HARMONY registry, a big data project that uniquely provides real-world as well as clinical trial findings from diverse APL patient populations.

They identified 937 patients in the registry with newly diagnosed APL between 2007 and 2020 who met the study’s data quality criteria, including 536 (57.2%) patients from two clinical trials, the UK AML-17 and GIMEMA APL0406 trials, and 401 (42.8%) patients from national registries in 6 countries, representing real-world data.

The median duration of follow-up was 5.66 years, with a range of 0-14 years.

The patients had an average age of about 50, which is consistent with the lower age of diagnosis typical of APL, compared with other forms of AML.

Among them, 380 (40.6%) were treated with the ATRA-ATO regimen while 509 (54.3%) received the chemotherapy combination of ATRA-Idarubicin (AIDA).

Overall, 37.8% were determined to be low risk, as assessed by the Sanz risk-score; 42.3% were intermediate risk, and 18.7% were considered high risk. The rate of complete remission among the patients was 87.5%, and 9% had relapsed.

The results showed the 10-year overall survival (OS) rate to be 92% among the chemo-free ATRA-ATO-treated patients versus 75% in the AIDA-treated patients (P = .001).

Likewise, those treated with the chemo-free regimen had a higher event-free survival and a lower cumulative incidence of relapse (CIR) versus chemotherapy over 10 years (P < .001 for both).

In further stratifying by risk, patients who were low risk also had greater improvements with the chemo-free regimen in overall survival (P = .004), event-free survival, and CIR versus AIDA treatment (P < .001).

Among high-risk patients, however, only event-free survival was significantly improved in the chemo-free treated patients (P = .046).

Older age stood out as a significant determinant of survival, with patients in the age 50-69 and 70 or over age groups having a significantly lower rate of overall survival and event-free survival, compared with those under 50 years of age (P < .001), with those risks observed regardless of treatment type.

Age was not a significant factor in terms of the incidence of relapse (P = .159).
 

Clinical trial versus real-world outcomes

Of note, improved outcomes were reported in clinical trials versus real-world data, with overall survival higher in clinical trials among patients receiving the ATRA/ATO chemo-free treatment (P = .025), as well as in those receiving the AIDA chemotherapy (P < .001).

Early death, an uncommon but key concern with APL, usually due to bleeding complications and defined as death occurring within 30 days from APL diagnosis, occurred among 56 patients, or 5.9%, overall, and was significantly higher in the age 50-69 and over 70 groups versus those under 50 (P < .001).

Early death was more common among those with a Sanz high-risk score (15.4%), compared with low or intermediate risk (3.9%; P < .001); however, the risk was no different between the chemo-free (3.4%) and chemotherapy (5.7%) groups, regardless of whether patients had a low or high risk.

The rates of early death were significantly higher in the real-world population (10.2%), compared with patients in clinical trials (2.8%; P < .001), which Dr. Voso noted may be expected, as early deaths in some cases can occur even before a diagnosis is made.

“These patients sometimes come to the ER and if a diagnosis is not made, they may die before even receiving treatment,” she said in a press briefing.

“Indeed, the median time to death among those who had early death in the study was only 10 days, and there were even some patients dying at day 0,” she explained.

“So, it’s very important that not only hematologists but emergency doctors recognize this disease and try to reduce the early death rate.”

Overall, the results all remained consistent after adjustment in a multivariate analysis, Dr. Voso said.

“The multivariate analysis confirmed that increasing age, high Sanz risk score, the real-life treatment scenario, and the chemotherapy-based approach are independently associated with decreased survival,” she said.

The findings underscore that “elderly age and high Sanz risk score significantly impact on the rate of early deaths, irrespective of treatment,” Dr. Voso said.
 

ATRA/ATO ‘gold standard’ for low/intermediate risk

Commenting on the study, Alessandro Isidori, MD, PhD, a hematologist at AORMN Hospital, in Pesaro, Italy, who moderated the session, noted that the study underscores the greater challenges with higher-risk patients.

“The study did not show a statistical benefit for high-risk patients receiving ATRA/ATO versus AIDA,” he told this news organization, noting that “currently, there are many countries where ATRA/ATO is not approved for use in high-risk APL.”

“In high-risk APL, the AIDA combination should still be preferred to ATRA/ATO,” he said.

Dr. Isidori recommended careful efforts to stratify higher-risk patients who still may benefit from ATRA/ATO.

“The analysis of high-risk patients with white blood cell count as a continuous variable instead of a fixed variable (more or less than 10,000/mmc) may help to discriminate some high-risk patients who could benefit from ATRA/ATO,” he noted.

Overall, however, “ATRA/ATO is the gold standard for low and intermediate risk APL,” he said.

“Although promising, more data are needed to confirm the efficacy of ATRA/ATO in high-risk APL.”

Dr. Voso disclosed ties with companies including Celgene/Bristol Myers Squibb, Astellas, Jazz Pharmaceuticals, Abbvie, Novartis, and AstraZeneca. Dr. Isidori reported no disclosures.
 

Patients with acute promyelocytic leukemia (APL) – previously considered among the most rapidly fatal forms of acute myeloid leukemia (AML) – now show survival rates exceeding 90% at 10 years after treatment with a chemotherapy-free regimen of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), with a survival advantage over ATRA plus chemotherapy in low- and intermediate-risk patients.

“In a large cohort of patients with APL, the chemo-free combination of ATRA/ATO is confirmed as the best treatment option, prolonging overall and event-free survival and reducing the relapse rate compared with ATRA/chemotherapy,” said first author Maria Teresa Voso, MD, of Tor Vergata University, in Rome, in presenting the findings at the 2023 annual meeting of the European Hematology Association.

APL, though rare, makes up about 10% of new AML cases, and the advent of the chemo-free ATRA-ATO regimen in recent years has transformed the disease, significantly improving survival.

However, with ongoing questions regarding factors associated with treatment benefits based on issues including the level of risk, Dr. Voso and colleagues turned to data from the large European Union–funded HARMONY registry, a big data project that uniquely provides real-world as well as clinical trial findings from diverse APL patient populations.

They identified 937 patients in the registry with newly diagnosed APL between 2007 and 2020 who met the study’s data quality criteria, including 536 (57.2%) patients from two clinical trials, the UK AML-17 and GIMEMA APL0406 trials, and 401 (42.8%) patients from national registries in 6 countries, representing real-world data.

The median duration of follow-up was 5.66 years, with a range of 0-14 years.

The patients had an average age of about 50, which is consistent with the lower age of diagnosis typical of APL, compared with other forms of AML.

Among them, 380 (40.6%) were treated with the ATRA-ATO regimen while 509 (54.3%) received the chemotherapy combination of ATRA-Idarubicin (AIDA).

Overall, 37.8% were determined to be low risk, as assessed by the Sanz risk-score; 42.3% were intermediate risk, and 18.7% were considered high risk. The rate of complete remission among the patients was 87.5%, and 9% had relapsed.

The results showed the 10-year overall survival (OS) rate to be 92% among the chemo-free ATRA-ATO-treated patients versus 75% in the AIDA-treated patients (P = .001).

Likewise, those treated with the chemo-free regimen had a higher event-free survival and a lower cumulative incidence of relapse (CIR) versus chemotherapy over 10 years (P < .001 for both).

In further stratifying by risk, patients who were low risk also had greater improvements with the chemo-free regimen in overall survival (P = .004), event-free survival, and CIR versus AIDA treatment (P < .001).

Among high-risk patients, however, only event-free survival was significantly improved in the chemo-free treated patients (P = .046).

Older age stood out as a significant determinant of survival, with patients in the age 50-69 and 70 or over age groups having a significantly lower rate of overall survival and event-free survival, compared with those under 50 years of age (P < .001), with those risks observed regardless of treatment type.

Age was not a significant factor in terms of the incidence of relapse (P = .159).
 

Clinical trial versus real-world outcomes

Of note, improved outcomes were reported in clinical trials versus real-world data, with overall survival higher in clinical trials among patients receiving the ATRA/ATO chemo-free treatment (P = .025), as well as in those receiving the AIDA chemotherapy (P < .001).

Early death, an uncommon but key concern with APL, usually due to bleeding complications and defined as death occurring within 30 days from APL diagnosis, occurred among 56 patients, or 5.9%, overall, and was significantly higher in the age 50-69 and over 70 groups versus those under 50 (P < .001).

Early death was more common among those with a Sanz high-risk score (15.4%), compared with low or intermediate risk (3.9%; P < .001); however, the risk was no different between the chemo-free (3.4%) and chemotherapy (5.7%) groups, regardless of whether patients had a low or high risk.

The rates of early death were significantly higher in the real-world population (10.2%), compared with patients in clinical trials (2.8%; P < .001), which Dr. Voso noted may be expected, as early deaths in some cases can occur even before a diagnosis is made.

“These patients sometimes come to the ER and if a diagnosis is not made, they may die before even receiving treatment,” she said in a press briefing.

“Indeed, the median time to death among those who had early death in the study was only 10 days, and there were even some patients dying at day 0,” she explained.

“So, it’s very important that not only hematologists but emergency doctors recognize this disease and try to reduce the early death rate.”

Overall, the results all remained consistent after adjustment in a multivariate analysis, Dr. Voso said.

“The multivariate analysis confirmed that increasing age, high Sanz risk score, the real-life treatment scenario, and the chemotherapy-based approach are independently associated with decreased survival,” she said.

The findings underscore that “elderly age and high Sanz risk score significantly impact on the rate of early deaths, irrespective of treatment,” Dr. Voso said.
 

ATRA/ATO ‘gold standard’ for low/intermediate risk

Commenting on the study, Alessandro Isidori, MD, PhD, a hematologist at AORMN Hospital, in Pesaro, Italy, who moderated the session, noted that the study underscores the greater challenges with higher-risk patients.

“The study did not show a statistical benefit for high-risk patients receiving ATRA/ATO versus AIDA,” he told this news organization, noting that “currently, there are many countries where ATRA/ATO is not approved for use in high-risk APL.”

“In high-risk APL, the AIDA combination should still be preferred to ATRA/ATO,” he said.

Dr. Isidori recommended careful efforts to stratify higher-risk patients who still may benefit from ATRA/ATO.

“The analysis of high-risk patients with white blood cell count as a continuous variable instead of a fixed variable (more or less than 10,000/mmc) may help to discriminate some high-risk patients who could benefit from ATRA/ATO,” he noted.

Overall, however, “ATRA/ATO is the gold standard for low and intermediate risk APL,” he said.

“Although promising, more data are needed to confirm the efficacy of ATRA/ATO in high-risk APL.”

Dr. Voso disclosed ties with companies including Celgene/Bristol Myers Squibb, Astellas, Jazz Pharmaceuticals, Abbvie, Novartis, and AstraZeneca. Dr. Isidori reported no disclosures.
 

Patients with acute promyelocytic leukemia (APL) – previously considered among the most rapidly fatal forms of acute myeloid leukemia (AML) – now show survival rates exceeding 90% at 10 years after treatment with a chemotherapy-free regimen of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), with a survival advantage over ATRA plus chemotherapy in low- and intermediate-risk patients.

“In a large cohort of patients with APL, the chemo-free combination of ATRA/ATO is confirmed as the best treatment option, prolonging overall and event-free survival and reducing the relapse rate compared with ATRA/chemotherapy,” said first author Maria Teresa Voso, MD, of Tor Vergata University, in Rome, in presenting the findings at the 2023 annual meeting of the European Hematology Association.

APL, though rare, makes up about 10% of new AML cases, and the advent of the chemo-free ATRA-ATO regimen in recent years has transformed the disease, significantly improving survival.

However, with ongoing questions regarding factors associated with treatment benefits based on issues including the level of risk, Dr. Voso and colleagues turned to data from the large European Union–funded HARMONY registry, a big data project that uniquely provides real-world as well as clinical trial findings from diverse APL patient populations.

They identified 937 patients in the registry with newly diagnosed APL between 2007 and 2020 who met the study’s data quality criteria, including 536 (57.2%) patients from two clinical trials, the UK AML-17 and GIMEMA APL0406 trials, and 401 (42.8%) patients from national registries in 6 countries, representing real-world data.

The median duration of follow-up was 5.66 years, with a range of 0-14 years.

The patients had an average age of about 50, which is consistent with the lower age of diagnosis typical of APL, compared with other forms of AML.

Among them, 380 (40.6%) were treated with the ATRA-ATO regimen while 509 (54.3%) received the chemotherapy combination of ATRA-Idarubicin (AIDA).

Overall, 37.8% were determined to be low risk, as assessed by the Sanz risk-score; 42.3% were intermediate risk, and 18.7% were considered high risk. The rate of complete remission among the patients was 87.5%, and 9% had relapsed.

The results showed the 10-year overall survival (OS) rate to be 92% among the chemo-free ATRA-ATO-treated patients versus 75% in the AIDA-treated patients (P = .001).

Likewise, those treated with the chemo-free regimen had a higher event-free survival and a lower cumulative incidence of relapse (CIR) versus chemotherapy over 10 years (P < .001 for both).

In further stratifying by risk, patients who were low risk also had greater improvements with the chemo-free regimen in overall survival (P = .004), event-free survival, and CIR versus AIDA treatment (P < .001).

Among high-risk patients, however, only event-free survival was significantly improved in the chemo-free treated patients (P = .046).

Older age stood out as a significant determinant of survival, with patients in the age 50-69 and 70 or over age groups having a significantly lower rate of overall survival and event-free survival, compared with those under 50 years of age (P < .001), with those risks observed regardless of treatment type.

Age was not a significant factor in terms of the incidence of relapse (P = .159).
 

Clinical trial versus real-world outcomes

Of note, improved outcomes were reported in clinical trials versus real-world data, with overall survival higher in clinical trials among patients receiving the ATRA/ATO chemo-free treatment (P = .025), as well as in those receiving the AIDA chemotherapy (P < .001).

Early death, an uncommon but key concern with APL, usually due to bleeding complications and defined as death occurring within 30 days from APL diagnosis, occurred among 56 patients, or 5.9%, overall, and was significantly higher in the age 50-69 and over 70 groups versus those under 50 (P < .001).

Early death was more common among those with a Sanz high-risk score (15.4%), compared with low or intermediate risk (3.9%; P < .001); however, the risk was no different between the chemo-free (3.4%) and chemotherapy (5.7%) groups, regardless of whether patients had a low or high risk.

The rates of early death were significantly higher in the real-world population (10.2%), compared with patients in clinical trials (2.8%; P < .001), which Dr. Voso noted may be expected, as early deaths in some cases can occur even before a diagnosis is made.

“These patients sometimes come to the ER and if a diagnosis is not made, they may die before even receiving treatment,” she said in a press briefing.

“Indeed, the median time to death among those who had early death in the study was only 10 days, and there were even some patients dying at day 0,” she explained.

“So, it’s very important that not only hematologists but emergency doctors recognize this disease and try to reduce the early death rate.”

Overall, the results all remained consistent after adjustment in a multivariate analysis, Dr. Voso said.

“The multivariate analysis confirmed that increasing age, high Sanz risk score, the real-life treatment scenario, and the chemotherapy-based approach are independently associated with decreased survival,” she said.

The findings underscore that “elderly age and high Sanz risk score significantly impact on the rate of early deaths, irrespective of treatment,” Dr. Voso said.
 

ATRA/ATO ‘gold standard’ for low/intermediate risk

Commenting on the study, Alessandro Isidori, MD, PhD, a hematologist at AORMN Hospital, in Pesaro, Italy, who moderated the session, noted that the study underscores the greater challenges with higher-risk patients.

“The study did not show a statistical benefit for high-risk patients receiving ATRA/ATO versus AIDA,” he told this news organization, noting that “currently, there are many countries where ATRA/ATO is not approved for use in high-risk APL.”

“In high-risk APL, the AIDA combination should still be preferred to ATRA/ATO,” he said.

Dr. Isidori recommended careful efforts to stratify higher-risk patients who still may benefit from ATRA/ATO.

“The analysis of high-risk patients with white blood cell count as a continuous variable instead of a fixed variable (more or less than 10,000/mmc) may help to discriminate some high-risk patients who could benefit from ATRA/ATO,” he noted.

Overall, however, “ATRA/ATO is the gold standard for low and intermediate risk APL,” he said.

“Although promising, more data are needed to confirm the efficacy of ATRA/ATO in high-risk APL.”

Dr. Voso disclosed ties with companies including Celgene/Bristol Myers Squibb, Astellas, Jazz Pharmaceuticals, Abbvie, Novartis, and AstraZeneca. Dr. Isidori reported no disclosures.
 

Delivering microdose incision-site injections of clindamycin significantly reduced the rate of surgical site infections (SSIs) in skin cancer surgery.

However, prophylaxis with flucloxacillin did not significantly lower SSI rates, compared with not using incision site antibiotics.

The rate of postoperative SSIs was 2.1% in the clindamycin arm, vs. 5.7% in the control arm and 5.3% in the flucloxacillin arm.

“Based on these results, we recommend the routine adoption of incisional microdosed clindamycin for patients undergoing skin cancer surgery,” Maple Goh, MBChB, of the Auckland Regional Plastic and Reconstructive Surgery Unit, Auckland, New Zealand, and the coauthors conclude. “This strategy appears suitable for widespread implementation because of the magnitude of the effect observed and the absence of adverse events.”

The study was published online in JAMA Surgery.

Skin cancer surgery carries a high risk of SSIs, which represent costly yet largely preventable complications of surgery. Despite the risk, there’s a lack of evidence from randomized clinical trials of the role of antibiotic prophylaxis in reducing SSI rates among patients undergoing skin cancer surgery. Previous studies have investigated incisional antibiotic prophylaxis to reduce SSIs with Mohs micrographic surgery, but these surgeries represent a relatively small proportion of overall skin cancer surgeries.

To understand whether this benefit extends to more general skin cancer surgeries, investigators recruited patients from a high-volume skin cancer center in New Zealand who were treated from February to July 2019. In the double-blind, prospective PICASSo trial, patients were randomly assigned to receive an incision site injection of buffered local anesthetic alone (control group), buffered local anesthetic with microdoses of flucloxacillin (500 mcg/mL), or buffered local anesthetic with microdoses of clindamycin (500 mcg/mL). The most common surgery type was excision and direct closure (approximately 80% in all arms), and the mean volume injected per length of direct closure was 1.5 mL/cm.

The primary endpoint was the rate of postoperative SSIs, defined as a postoperative wound infection score of 5 or more. The SSI rate was calculated as the number of lesions with SSIs per total number of lesions in the group.

Overall, 681 patients with 1,133 total lesions were included in the study. Compared with the control arm, the rate of postoperative SSIs was nearly threefold lower among patients who received clindamycin, –2.1% (9 of 422) vs. 5.7% (22 of 388) in the control arm (P = .01 for clindamycin vs. control).

However, flucloxacillin did not demonstrate the same effectiveness. The flucloxacillin arm and the control arm demonstrated similar postoperative SSI rates – 5.3% (17 of 323) vs. 5.7%.

The results were similar after adjusting for baseline differences and lesion ulceration.

The researchers also found that the proportion of lesions that required postoperative systemic antibiotics was four times higher among the control arm, in comparison with the clindamycin arm (8% vs. 2.1%; P < .001). It was two times higher than in the flucloxacillin arm (8% vs. 4%; P = .03).

Treatment with microdoses of incisional flucloxacillin and clindamycin was safe and well tolerated.

The researchers speculated that clindamycin’s greater effectiveness may come down to its slightly broader coverage of commonly cultured bacteria in skin and soft tissue infections, including community-associated methicillin-resistant Staphylococcus aureus. Clindamycin is known to have more efficacy against anaerobic bacteria that may be lurking in chronically ulcerated skin lesions and is associated with less local tissue inflammation, compared with flucloxacillin.

Overall, “clindamycin was significantly more effective at preventing SSI than flucloxacillin in our study,” the authors conclude. They note that the use of clindamycin as a first-line prophylaxis agent against SSIs for patients undergoing skin cancer surgery is a practical option.

“These results establish evidence-based guidelines for antibiotic prophylaxis in one of the most common surgical interventions performed worldwide, where they have been previously absent,” the researchers say.

The authors of an editorial published with the study underscore other advantages of incisional microdosing with antibiotics.

“One advantage of cutaneous antibiotic administration is improved drug delivery to poorly perfused tissue, which would have limited reach by the systemic circulation,” wrote Amanda R. Sergesketter, MD, of Duke University, Durham, N.C., and Scott T. Hollenbeck, MD, of the University of Virginia, Charlottesville.

“While not evaluated in this study, local antibiotic delivery may be especially relevant to larger and more complex wounds,” the editorialists say. They note that the next step for future studies should be to evaluate prophylaxis in more complex situations.

“Such studies should be considered enthusiastically, given the clearly favorable impact on surgical site infections demonstrated in the PICASSo trial,” Dr. Sergesketter and Dr. Hollenbeck said.

The study was supported by a grant from the New Zealand Health Research Council. Dr. Hollenbeck reported educational grants to Duke University from Allergan, Acelity, Synovis, Integra, Smith & Nephew, Stryker, Cook, KLs Martin, Bard, VOptix, Scanlan, True Digital Surgery, Nautilus, Mitaka, Checkpoint Surgical, and Omniguide, and he is a founder and equity holder for InSoma Bio, a premarket company focused on tissue regeneration.

A version of this article first appeared on Medscape.com.

Delivering microdose incision-site injections of clindamycin significantly reduced the rate of surgical site infections (SSIs) in skin cancer surgery.

However, prophylaxis with flucloxacillin did not significantly lower SSI rates, compared with not using incision site antibiotics.

The rate of postoperative SSIs was 2.1% in the clindamycin arm, vs. 5.7% in the control arm and 5.3% in the flucloxacillin arm.

“Based on these results, we recommend the routine adoption of incisional microdosed clindamycin for patients undergoing skin cancer surgery,” Maple Goh, MBChB, of the Auckland Regional Plastic and Reconstructive Surgery Unit, Auckland, New Zealand, and the coauthors conclude. “This strategy appears suitable for widespread implementation because of the magnitude of the effect observed and the absence of adverse events.”

The study was published online in JAMA Surgery.

Skin cancer surgery carries a high risk of SSIs, which represent costly yet largely preventable complications of surgery. Despite the risk, there’s a lack of evidence from randomized clinical trials of the role of antibiotic prophylaxis in reducing SSI rates among patients undergoing skin cancer surgery. Previous studies have investigated incisional antibiotic prophylaxis to reduce SSIs with Mohs micrographic surgery, but these surgeries represent a relatively small proportion of overall skin cancer surgeries.

To understand whether this benefit extends to more general skin cancer surgeries, investigators recruited patients from a high-volume skin cancer center in New Zealand who were treated from February to July 2019. In the double-blind, prospective PICASSo trial, patients were randomly assigned to receive an incision site injection of buffered local anesthetic alone (control group), buffered local anesthetic with microdoses of flucloxacillin (500 mcg/mL), or buffered local anesthetic with microdoses of clindamycin (500 mcg/mL). The most common surgery type was excision and direct closure (approximately 80% in all arms), and the mean volume injected per length of direct closure was 1.5 mL/cm.

The primary endpoint was the rate of postoperative SSIs, defined as a postoperative wound infection score of 5 or more. The SSI rate was calculated as the number of lesions with SSIs per total number of lesions in the group.

Overall, 681 patients with 1,133 total lesions were included in the study. Compared with the control arm, the rate of postoperative SSIs was nearly threefold lower among patients who received clindamycin, –2.1% (9 of 422) vs. 5.7% (22 of 388) in the control arm (P = .01 for clindamycin vs. control).

However, flucloxacillin did not demonstrate the same effectiveness. The flucloxacillin arm and the control arm demonstrated similar postoperative SSI rates – 5.3% (17 of 323) vs. 5.7%.

The results were similar after adjusting for baseline differences and lesion ulceration.

The researchers also found that the proportion of lesions that required postoperative systemic antibiotics was four times higher among the control arm, in comparison with the clindamycin arm (8% vs. 2.1%; P < .001). It was two times higher than in the flucloxacillin arm (8% vs. 4%; P = .03).

Treatment with microdoses of incisional flucloxacillin and clindamycin was safe and well tolerated.

The researchers speculated that clindamycin’s greater effectiveness may come down to its slightly broader coverage of commonly cultured bacteria in skin and soft tissue infections, including community-associated methicillin-resistant Staphylococcus aureus. Clindamycin is known to have more efficacy against anaerobic bacteria that may be lurking in chronically ulcerated skin lesions and is associated with less local tissue inflammation, compared with flucloxacillin.

Overall, “clindamycin was significantly more effective at preventing SSI than flucloxacillin in our study,” the authors conclude. They note that the use of clindamycin as a first-line prophylaxis agent against SSIs for patients undergoing skin cancer surgery is a practical option.

“These results establish evidence-based guidelines for antibiotic prophylaxis in one of the most common surgical interventions performed worldwide, where they have been previously absent,” the researchers say.

The authors of an editorial published with the study underscore other advantages of incisional microdosing with antibiotics.

“One advantage of cutaneous antibiotic administration is improved drug delivery to poorly perfused tissue, which would have limited reach by the systemic circulation,” wrote Amanda R. Sergesketter, MD, of Duke University, Durham, N.C., and Scott T. Hollenbeck, MD, of the University of Virginia, Charlottesville.

“While not evaluated in this study, local antibiotic delivery may be especially relevant to larger and more complex wounds,” the editorialists say. They note that the next step for future studies should be to evaluate prophylaxis in more complex situations.

“Such studies should be considered enthusiastically, given the clearly favorable impact on surgical site infections demonstrated in the PICASSo trial,” Dr. Sergesketter and Dr. Hollenbeck said.

The study was supported by a grant from the New Zealand Health Research Council. Dr. Hollenbeck reported educational grants to Duke University from Allergan, Acelity, Synovis, Integra, Smith & Nephew, Stryker, Cook, KLs Martin, Bard, VOptix, Scanlan, True Digital Surgery, Nautilus, Mitaka, Checkpoint Surgical, and Omniguide, and he is a founder and equity holder for InSoma Bio, a premarket company focused on tissue regeneration.

A version of this article first appeared on Medscape.com.

Delivering microdose incision-site injections of clindamycin significantly reduced the rate of surgical site infections (SSIs) in skin cancer surgery.

However, prophylaxis with flucloxacillin did not significantly lower SSI rates, compared with not using incision site antibiotics.

The rate of postoperative SSIs was 2.1% in the clindamycin arm, vs. 5.7% in the control arm and 5.3% in the flucloxacillin arm.

“Based on these results, we recommend the routine adoption of incisional microdosed clindamycin for patients undergoing skin cancer surgery,” Maple Goh, MBChB, of the Auckland Regional Plastic and Reconstructive Surgery Unit, Auckland, New Zealand, and the coauthors conclude. “This strategy appears suitable for widespread implementation because of the magnitude of the effect observed and the absence of adverse events.”

The study was published online in JAMA Surgery.

Skin cancer surgery carries a high risk of SSIs, which represent costly yet largely preventable complications of surgery. Despite the risk, there’s a lack of evidence from randomized clinical trials of the role of antibiotic prophylaxis in reducing SSI rates among patients undergoing skin cancer surgery. Previous studies have investigated incisional antibiotic prophylaxis to reduce SSIs with Mohs micrographic surgery, but these surgeries represent a relatively small proportion of overall skin cancer surgeries.

To understand whether this benefit extends to more general skin cancer surgeries, investigators recruited patients from a high-volume skin cancer center in New Zealand who were treated from February to July 2019. In the double-blind, prospective PICASSo trial, patients were randomly assigned to receive an incision site injection of buffered local anesthetic alone (control group), buffered local anesthetic with microdoses of flucloxacillin (500 mcg/mL), or buffered local anesthetic with microdoses of clindamycin (500 mcg/mL). The most common surgery type was excision and direct closure (approximately 80% in all arms), and the mean volume injected per length of direct closure was 1.5 mL/cm.

The primary endpoint was the rate of postoperative SSIs, defined as a postoperative wound infection score of 5 or more. The SSI rate was calculated as the number of lesions with SSIs per total number of lesions in the group.

Overall, 681 patients with 1,133 total lesions were included in the study. Compared with the control arm, the rate of postoperative SSIs was nearly threefold lower among patients who received clindamycin, –2.1% (9 of 422) vs. 5.7% (22 of 388) in the control arm (P = .01 for clindamycin vs. control).

However, flucloxacillin did not demonstrate the same effectiveness. The flucloxacillin arm and the control arm demonstrated similar postoperative SSI rates – 5.3% (17 of 323) vs. 5.7%.

The results were similar after adjusting for baseline differences and lesion ulceration.

The researchers also found that the proportion of lesions that required postoperative systemic antibiotics was four times higher among the control arm, in comparison with the clindamycin arm (8% vs. 2.1%; P < .001). It was two times higher than in the flucloxacillin arm (8% vs. 4%; P = .03).

Treatment with microdoses of incisional flucloxacillin and clindamycin was safe and well tolerated.

The researchers speculated that clindamycin’s greater effectiveness may come down to its slightly broader coverage of commonly cultured bacteria in skin and soft tissue infections, including community-associated methicillin-resistant Staphylococcus aureus. Clindamycin is known to have more efficacy against anaerobic bacteria that may be lurking in chronically ulcerated skin lesions and is associated with less local tissue inflammation, compared with flucloxacillin.

Overall, “clindamycin was significantly more effective at preventing SSI than flucloxacillin in our study,” the authors conclude. They note that the use of clindamycin as a first-line prophylaxis agent against SSIs for patients undergoing skin cancer surgery is a practical option.

“These results establish evidence-based guidelines for antibiotic prophylaxis in one of the most common surgical interventions performed worldwide, where they have been previously absent,” the researchers say.

The authors of an editorial published with the study underscore other advantages of incisional microdosing with antibiotics.

“One advantage of cutaneous antibiotic administration is improved drug delivery to poorly perfused tissue, which would have limited reach by the systemic circulation,” wrote Amanda R. Sergesketter, MD, of Duke University, Durham, N.C., and Scott T. Hollenbeck, MD, of the University of Virginia, Charlottesville.

“While not evaluated in this study, local antibiotic delivery may be especially relevant to larger and more complex wounds,” the editorialists say. They note that the next step for future studies should be to evaluate prophylaxis in more complex situations.

“Such studies should be considered enthusiastically, given the clearly favorable impact on surgical site infections demonstrated in the PICASSo trial,” Dr. Sergesketter and Dr. Hollenbeck said.

The study was supported by a grant from the New Zealand Health Research Council. Dr. Hollenbeck reported educational grants to Duke University from Allergan, Acelity, Synovis, Integra, Smith & Nephew, Stryker, Cook, KLs Martin, Bard, VOptix, Scanlan, True Digital Surgery, Nautilus, Mitaka, Checkpoint Surgical, and Omniguide, and he is a founder and equity holder for InSoma Bio, a premarket company focused on tissue regeneration.

A version of this article first appeared on Medscape.com.

At a median follow-up of 47.2 months, axicabtagene ciloleucel (axi-cel, Yescarta) significantly improved overall survival compared with standard second-line treatments in patients with early relapsed or refractory large B-cell lymphoma, according to a phase 3 investigation reported at the annual meeting of the American Society of Clinical Oncology (ASCO).

The anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy was approved for second-line treatment in 2022 based on better event-free survival, but standard second-line treatment – chemoimmunotherapy followed by high-dose chemotherapy and autologous stem-cell transplant in responders – still remains the prevailing approach, explained Jason Westin, MD, director of lymphoma research at MD Anderson Cancer Center, Houston. Dr. Westin, lead investigator, presented the trial, dubbed ZUMA-7, at the ASCO meeting.

The new findings might change that. ZUMA-7 “conclusively demonstrates that trying chemotherapy in the second line and saving cell therapy for the third line is an inferior approach ... ZUMA-7 confirms axi-cel is a second-line standard of care for patients with refractory or early relapsed large B cell lymphoma based on superior overall survival,” said Dr. Westin.

Study discussant Asher A. Chanan-Khan, MD, a CAR-T specialist at the Mayo Clinic in Jacksonville, Fla., agreed.

“This data must alter the current standard of care making CAR-T or axi-cel, based on the data we heard, a preferred second-line treatment ... Moving CAR-T earlier in the treatment paradigm is likely a better choice for our patients,” he said.

The study was published in the New England Journal of Medicine to coincide with the presentations.

Dr. Westin noted that axi-cel is now under investigation in ZUMA-23 for first-line treatment of high-risk large B-cell lymphoma (LBCL).


 

Study details

Zuma-7 randomized 180 LBCL patients to a one-time axi-cel infusion and 179 to standard care. Patients were refractory to first line chemoimmunotherapy or had relapsed within 12 months; just 36% of patients in the standard care group did well enough on treatment to go on to stem-cell transplant.

Median progression-free survival (PFS) was 14.7 months with axi-cel versus 3.7 months with standard care.

Significantly, the better PFS appears to have translated into better overall survival (OS).

At a median of almost 4 years, 82 patients in the axi-cel group had died, compared with 95 patients with standard care who had died. Estimated 4-year OS was 54.6% with axi-cel versus 46% with standard care (HR 0.73, P = .03).

The OS benefit held in high-risk subgroups, including patients over 64 years old, those refractory to first-line treatment, and patients with high-grade disease.

Adverse events were in keeping with labeling. Cytokine release syndrome was more common in the axi-cel arm, including grade 3 or worse CRS in 6% of axi-cel patients versus none on standard care. Grade 3 or worse infections were also more common at 16.5% versus 11.9% with standard care. Over 11% of axi-cel patients developed hypogammaglobulinemia versus 0.6% in the standard care group.

Overall, there were no new serious or fatal adverse events since the initial PFS results were reported in 2022, when eight fatal adverse events were reported with axi-cel versus two with standard care.

The work was funded by axi-cel maker Kite Pharma, a subsidiary of Gilead. Investigators included Kite/Gilead employees and others who reported financial relationships with the companies, including Dr. Westin, a Kite/Gilead researcher and adviser. Dr. Chanan-Khan disclosed ties with Cellectar, Starton Therapeutics, Ascentage Pharma, and others.

At a median follow-up of 47.2 months, axicabtagene ciloleucel (axi-cel, Yescarta) significantly improved overall survival compared with standard second-line treatments in patients with early relapsed or refractory large B-cell lymphoma, according to a phase 3 investigation reported at the annual meeting of the American Society of Clinical Oncology (ASCO).

The anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy was approved for second-line treatment in 2022 based on better event-free survival, but standard second-line treatment – chemoimmunotherapy followed by high-dose chemotherapy and autologous stem-cell transplant in responders – still remains the prevailing approach, explained Jason Westin, MD, director of lymphoma research at MD Anderson Cancer Center, Houston. Dr. Westin, lead investigator, presented the trial, dubbed ZUMA-7, at the ASCO meeting.

The new findings might change that. ZUMA-7 “conclusively demonstrates that trying chemotherapy in the second line and saving cell therapy for the third line is an inferior approach ... ZUMA-7 confirms axi-cel is a second-line standard of care for patients with refractory or early relapsed large B cell lymphoma based on superior overall survival,” said Dr. Westin.

Study discussant Asher A. Chanan-Khan, MD, a CAR-T specialist at the Mayo Clinic in Jacksonville, Fla., agreed.

“This data must alter the current standard of care making CAR-T or axi-cel, based on the data we heard, a preferred second-line treatment ... Moving CAR-T earlier in the treatment paradigm is likely a better choice for our patients,” he said.

The study was published in the New England Journal of Medicine to coincide with the presentations.

Dr. Westin noted that axi-cel is now under investigation in ZUMA-23 for first-line treatment of high-risk large B-cell lymphoma (LBCL).


 

Study details

Zuma-7 randomized 180 LBCL patients to a one-time axi-cel infusion and 179 to standard care. Patients were refractory to first line chemoimmunotherapy or had relapsed within 12 months; just 36% of patients in the standard care group did well enough on treatment to go on to stem-cell transplant.

Median progression-free survival (PFS) was 14.7 months with axi-cel versus 3.7 months with standard care.

Significantly, the better PFS appears to have translated into better overall survival (OS).

At a median of almost 4 years, 82 patients in the axi-cel group had died, compared with 95 patients with standard care who had died. Estimated 4-year OS was 54.6% with axi-cel versus 46% with standard care (HR 0.73, P = .03).

The OS benefit held in high-risk subgroups, including patients over 64 years old, those refractory to first-line treatment, and patients with high-grade disease.

Adverse events were in keeping with labeling. Cytokine release syndrome was more common in the axi-cel arm, including grade 3 or worse CRS in 6% of axi-cel patients versus none on standard care. Grade 3 or worse infections were also more common at 16.5% versus 11.9% with standard care. Over 11% of axi-cel patients developed hypogammaglobulinemia versus 0.6% in the standard care group.

Overall, there were no new serious or fatal adverse events since the initial PFS results were reported in 2022, when eight fatal adverse events were reported with axi-cel versus two with standard care.

The work was funded by axi-cel maker Kite Pharma, a subsidiary of Gilead. Investigators included Kite/Gilead employees and others who reported financial relationships with the companies, including Dr. Westin, a Kite/Gilead researcher and adviser. Dr. Chanan-Khan disclosed ties with Cellectar, Starton Therapeutics, Ascentage Pharma, and others.

At a median follow-up of 47.2 months, axicabtagene ciloleucel (axi-cel, Yescarta) significantly improved overall survival compared with standard second-line treatments in patients with early relapsed or refractory large B-cell lymphoma, according to a phase 3 investigation reported at the annual meeting of the American Society of Clinical Oncology (ASCO).

The anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy was approved for second-line treatment in 2022 based on better event-free survival, but standard second-line treatment – chemoimmunotherapy followed by high-dose chemotherapy and autologous stem-cell transplant in responders – still remains the prevailing approach, explained Jason Westin, MD, director of lymphoma research at MD Anderson Cancer Center, Houston. Dr. Westin, lead investigator, presented the trial, dubbed ZUMA-7, at the ASCO meeting.

The new findings might change that. ZUMA-7 “conclusively demonstrates that trying chemotherapy in the second line and saving cell therapy for the third line is an inferior approach ... ZUMA-7 confirms axi-cel is a second-line standard of care for patients with refractory or early relapsed large B cell lymphoma based on superior overall survival,” said Dr. Westin.

Study discussant Asher A. Chanan-Khan, MD, a CAR-T specialist at the Mayo Clinic in Jacksonville, Fla., agreed.

“This data must alter the current standard of care making CAR-T or axi-cel, based on the data we heard, a preferred second-line treatment ... Moving CAR-T earlier in the treatment paradigm is likely a better choice for our patients,” he said.

The study was published in the New England Journal of Medicine to coincide with the presentations.

Dr. Westin noted that axi-cel is now under investigation in ZUMA-23 for first-line treatment of high-risk large B-cell lymphoma (LBCL).


 

Study details

Zuma-7 randomized 180 LBCL patients to a one-time axi-cel infusion and 179 to standard care. Patients were refractory to first line chemoimmunotherapy or had relapsed within 12 months; just 36% of patients in the standard care group did well enough on treatment to go on to stem-cell transplant.

Median progression-free survival (PFS) was 14.7 months with axi-cel versus 3.7 months with standard care.

Significantly, the better PFS appears to have translated into better overall survival (OS).

At a median of almost 4 years, 82 patients in the axi-cel group had died, compared with 95 patients with standard care who had died. Estimated 4-year OS was 54.6% with axi-cel versus 46% with standard care (HR 0.73, P = .03).

The OS benefit held in high-risk subgroups, including patients over 64 years old, those refractory to first-line treatment, and patients with high-grade disease.

Adverse events were in keeping with labeling. Cytokine release syndrome was more common in the axi-cel arm, including grade 3 or worse CRS in 6% of axi-cel patients versus none on standard care. Grade 3 or worse infections were also more common at 16.5% versus 11.9% with standard care. Over 11% of axi-cel patients developed hypogammaglobulinemia versus 0.6% in the standard care group.

Overall, there were no new serious or fatal adverse events since the initial PFS results were reported in 2022, when eight fatal adverse events were reported with axi-cel versus two with standard care.

The work was funded by axi-cel maker Kite Pharma, a subsidiary of Gilead. Investigators included Kite/Gilead employees and others who reported financial relationships with the companies, including Dr. Westin, a Kite/Gilead researcher and adviser. Dr. Chanan-Khan disclosed ties with Cellectar, Starton Therapeutics, Ascentage Pharma, and others.

Shortages of carboplatin and cisplatin have become widespread among major cancer centers, according to a survey released this week from the National Comprehensive Cancer Network.

The survey, which included responses from 27 NCCN member institutions, revealed that 93% are experiencing a shortage of carboplatin and that 70% have reported a shortage of cisplatin.

“This is an unacceptable situation,” Robert W. Carlson, MD, NCCN’s chief executive offer, said in the statement released by the network.

“We are hearing from oncologists and pharmacists across the country who have to scramble to find appropriate alternatives for treating their patients with cancer right now,” Dr. Carlson said. And while the survey results show patients are still able to get lifesaving care, “it comes at a burden to our overtaxed medical facilities.”

The NCCN called on the federal government, the pharmaceutical industry, providers, and payers to take steps to “help mitigate any impacts” from this cancer drug shortage.

“We need to work together to improve the current situation and prevent it from happening again in the future,” Dr. Carlson stressed.

Carboplatin and cisplatin, which are frequently used together for systemic treatment, are highly effective therapies prescribed to treat many cancer types, including lung, breast, and prostate cancers, as well as leukemias and lymphomas. An estimated 500,000 new patients with cancer receive these agents each year.

The current survey, conducted over the last week of May, found that 100% of responding centers are able to continue to treat patients who need cisplatin without delays.

The same cannot be said for carboplatin: only 64% of centers said they are still able to continue treating all current patients receiving the platinum-based therapy. Among 19 responding centers, 20% reported that they were continuing carboplatin regimens for some but not all patients. And 16% reported treatment delays from having to obtain prior authorization for modified treatment plans, though none reported denials.

“Carboplatin has been in short supply for months but in the last 4 weeks has reached a critical stage,” according to one survey comment. “Without additional inventory many of our sites will be out of drug by early next week.”

In response to the survey question, “Is your center experiencing a shortage of carboplatin,” others made similar comments:

• “Current shipments from established manufacturers have been paused.”
• “The supply of carboplatin available is not meeting our demands.”
• “Without additional supply in early June, we will have to implement several shortage mitigation strategies.”

Survey respondents also addressed whether manufacturers or suppliers have provided any indication of when these drugs will become readily available again. For both drugs, about 60% of respondents said no. And for those who do receive updates, many noted that the “information is tentative and variable.”

Respondents indicated that other cancer agents, including methotrexate (67%) and 5FU (26%), are also in short supply at their centers.

The shortage and the uncertainty as to when it will end are forcing some centers to develop conservation and mitigation strategies.

The NCCN has broadly outlined how the federal government, the pharmaceutical industry, providers, and payers can help with prevention and mitigation. The NCCN has called on the federal government and the pharmaceutical industry to work to secure a steady supply of core anticancer drugs and has asked payers to “put patients first and provide flexible and efficient systems of providing coverage for alternative therapies replacing anti-cancer drugs that are unavailable or in shortage.”

Overall, the survey results “demonstrate the widespread impact of the chemotherapy shortage,” said Alyssa Schatz, MSW, senior director of policy and advocacy for NCCN. “We hope that by sharing this survey and calling for united action across the oncology community, we can come together to prevent future drug shortages and ensure quality, effective, equitable, and accessible cancer care for all.”

A version of this article first appeared on Medscape.com.

Shortages of carboplatin and cisplatin have become widespread among major cancer centers, according to a survey released this week from the National Comprehensive Cancer Network.

The survey, which included responses from 27 NCCN member institutions, revealed that 93% are experiencing a shortage of carboplatin and that 70% have reported a shortage of cisplatin.

“This is an unacceptable situation,” Robert W. Carlson, MD, NCCN’s chief executive offer, said in the statement released by the network.

“We are hearing from oncologists and pharmacists across the country who have to scramble to find appropriate alternatives for treating their patients with cancer right now,” Dr. Carlson said. And while the survey results show patients are still able to get lifesaving care, “it comes at a burden to our overtaxed medical facilities.”

The NCCN called on the federal government, the pharmaceutical industry, providers, and payers to take steps to “help mitigate any impacts” from this cancer drug shortage.

“We need to work together to improve the current situation and prevent it from happening again in the future,” Dr. Carlson stressed.

Carboplatin and cisplatin, which are frequently used together for systemic treatment, are highly effective therapies prescribed to treat many cancer types, including lung, breast, and prostate cancers, as well as leukemias and lymphomas. An estimated 500,000 new patients with cancer receive these agents each year.

The current survey, conducted over the last week of May, found that 100% of responding centers are able to continue to treat patients who need cisplatin without delays.

The same cannot be said for carboplatin: only 64% of centers said they are still able to continue treating all current patients receiving the platinum-based therapy. Among 19 responding centers, 20% reported that they were continuing carboplatin regimens for some but not all patients. And 16% reported treatment delays from having to obtain prior authorization for modified treatment plans, though none reported denials.

“Carboplatin has been in short supply for months but in the last 4 weeks has reached a critical stage,” according to one survey comment. “Without additional inventory many of our sites will be out of drug by early next week.”

In response to the survey question, “Is your center experiencing a shortage of carboplatin,” others made similar comments:

• “Current shipments from established manufacturers have been paused.”
• “The supply of carboplatin available is not meeting our demands.”
• “Without additional supply in early June, we will have to implement several shortage mitigation strategies.”

Survey respondents also addressed whether manufacturers or suppliers have provided any indication of when these drugs will become readily available again. For both drugs, about 60% of respondents said no. And for those who do receive updates, many noted that the “information is tentative and variable.”

Respondents indicated that other cancer agents, including methotrexate (67%) and 5FU (26%), are also in short supply at their centers.

The shortage and the uncertainty as to when it will end are forcing some centers to develop conservation and mitigation strategies.

The NCCN has broadly outlined how the federal government, the pharmaceutical industry, providers, and payers can help with prevention and mitigation. The NCCN has called on the federal government and the pharmaceutical industry to work to secure a steady supply of core anticancer drugs and has asked payers to “put patients first and provide flexible and efficient systems of providing coverage for alternative therapies replacing anti-cancer drugs that are unavailable or in shortage.”

Overall, the survey results “demonstrate the widespread impact of the chemotherapy shortage,” said Alyssa Schatz, MSW, senior director of policy and advocacy for NCCN. “We hope that by sharing this survey and calling for united action across the oncology community, we can come together to prevent future drug shortages and ensure quality, effective, equitable, and accessible cancer care for all.”

A version of this article first appeared on Medscape.com.

Shortages of carboplatin and cisplatin have become widespread among major cancer centers, according to a survey released this week from the National Comprehensive Cancer Network.

The survey, which included responses from 27 NCCN member institutions, revealed that 93% are experiencing a shortage of carboplatin and that 70% have reported a shortage of cisplatin.

“This is an unacceptable situation,” Robert W. Carlson, MD, NCCN’s chief executive offer, said in the statement released by the network.

“We are hearing from oncologists and pharmacists across the country who have to scramble to find appropriate alternatives for treating their patients with cancer right now,” Dr. Carlson said. And while the survey results show patients are still able to get lifesaving care, “it comes at a burden to our overtaxed medical facilities.”

The NCCN called on the federal government, the pharmaceutical industry, providers, and payers to take steps to “help mitigate any impacts” from this cancer drug shortage.

“We need to work together to improve the current situation and prevent it from happening again in the future,” Dr. Carlson stressed.

Carboplatin and cisplatin, which are frequently used together for systemic treatment, are highly effective therapies prescribed to treat many cancer types, including lung, breast, and prostate cancers, as well as leukemias and lymphomas. An estimated 500,000 new patients with cancer receive these agents each year.

The current survey, conducted over the last week of May, found that 100% of responding centers are able to continue to treat patients who need cisplatin without delays.

The same cannot be said for carboplatin: only 64% of centers said they are still able to continue treating all current patients receiving the platinum-based therapy. Among 19 responding centers, 20% reported that they were continuing carboplatin regimens for some but not all patients. And 16% reported treatment delays from having to obtain prior authorization for modified treatment plans, though none reported denials.

“Carboplatin has been in short supply for months but in the last 4 weeks has reached a critical stage,” according to one survey comment. “Without additional inventory many of our sites will be out of drug by early next week.”

In response to the survey question, “Is your center experiencing a shortage of carboplatin,” others made similar comments:

• “Current shipments from established manufacturers have been paused.”
• “The supply of carboplatin available is not meeting our demands.”
• “Without additional supply in early June, we will have to implement several shortage mitigation strategies.”

Survey respondents also addressed whether manufacturers or suppliers have provided any indication of when these drugs will become readily available again. For both drugs, about 60% of respondents said no. And for those who do receive updates, many noted that the “information is tentative and variable.”

Respondents indicated that other cancer agents, including methotrexate (67%) and 5FU (26%), are also in short supply at their centers.

The shortage and the uncertainty as to when it will end are forcing some centers to develop conservation and mitigation strategies.

The NCCN has broadly outlined how the federal government, the pharmaceutical industry, providers, and payers can help with prevention and mitigation. The NCCN has called on the federal government and the pharmaceutical industry to work to secure a steady supply of core anticancer drugs and has asked payers to “put patients first and provide flexible and efficient systems of providing coverage for alternative therapies replacing anti-cancer drugs that are unavailable or in shortage.”

Overall, the survey results “demonstrate the widespread impact of the chemotherapy shortage,” said Alyssa Schatz, MSW, senior director of policy and advocacy for NCCN. “We hope that by sharing this survey and calling for united action across the oncology community, we can come together to prevent future drug shortages and ensure quality, effective, equitable, and accessible cancer care for all.”

A version of this article first appeared on Medscape.com.

Adult survivors of childhood cancer have an elevated risk of developing cognitive impairment years after their cancer diagnosis and treatment, new research shows.

Among more than 2,300 adult survivors of childhood cancer and their siblings, who served as controls, new-onset memory impairment emerged more often in survivors decades later.

The increased risk was associated with the cancer treatment that was provided as well as modifiable health behaviors and chronic health conditions.

Even 35 years after being diagnosed, cancer survivors who never received chemotherapies or radiation therapies known to damage the brain reported far greater memory impairment than did their siblings, first author Nicholas Phillips, MD, told this news organization.

What the findings suggest is that “we need to educate oncologists and primary care providers on the risks our survivors face long after completion of therapy,” said Dr. Phillips, of the epidemiology and cancer control department at St. Jude Children’s Research Hospital, Memphis, Tenn.

The study was published online in JAMA Network Open.

Cancer survivors face an elevated risk for severe neurocognitive effects that can emerge 5-10 years following their diagnosis and treatment. However, it’s unclear whether new-onset neurocognitive problems can still develop a decade or more following diagnosis.

Over a long-term follow-up, Dr. Phillips and colleagues explored this question in 2,375 adult survivors of childhood cancer from the Childhood Cancer Survivor Study and 232 of their siblings.

Among the cancer cohort, 1,316 patients were survivors of acute lymphoblastic leukemia (ALL), 488 were survivors of central nervous system (CNS) tumors, and 571 had survived Hodgkin lymphoma.

The researchers determined the prevalence of new-onset neurocognitive impairment between baseline (23 years after diagnosis) and follow-up (35 years after diagnosis). New-onset neurocognitive impairment – present at follow-up but not at baseline – was defined as having a score in the worst 10% of the sibling cohort.

A higher proportion of survivors had new-onset memory impairment at follow-up compared with siblings. Specifically, about 8% of siblings had new-onset memory trouble, compared with 14% of ALL survivors treated with chemotherapy only, 26% of ALL survivors treated with cranial radiation, 35% of CNS tumor survivors, and 17% of Hodgkin lymphoma survivors.

New-onset memory impairment was associated with cranial radiation among CNS tumor survivors (relative risk [RR], 1.97) and alkylator chemotherapy at or above 8,000 mg/m² among survivors of ALL who were treated without cranial radiation (RR, 2.80). The authors also found that smoking, low educational attainment, and low physical activity were associated with an elevated risk for new-onset memory impairment.

Dr. Phillips noted that current guidelines emphasize the importance of short-term monitoring of a survivor’s neurocognitive status on the basis of that person’s chemotherapy and radiation exposures.

However, “our study suggests that all survivors, regardless of their therapy, should be screened regularly for new-onset neurocognitive problems. And this screening should be done regularly for decades after diagnosis,” he said in an interview.

Dr. Phillips also noted the importance of communicating lifestyle modifications, such as not smoking and maintaining an active lifestyle.

“We need to start early and use the power of repetition when communicating with our survivors and their families,” Dr. Phillips said. “When our families and survivors hear the word ‘exercise,’ they think of gym memberships, lifting weights, and running on treadmills. But what we really want our survivors to do is stay active.”

What this means is engaging for about 2.5 hours a week in a range of activities, such as ballet, basketball, volleyball, bicycling, or swimming.

“And if our kids want to quit after 3 months, let them know that this is okay. They just need to replace that activity with another activity,” said Dr. Phillips. “We want them to find a fun hobby that they will enjoy that will keep them active.”

The study was supported by the National Cancer Institute. Dr. Phillips has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Adult survivors of childhood cancer have an elevated risk of developing cognitive impairment years after their cancer diagnosis and treatment, new research shows.

Among more than 2,300 adult survivors of childhood cancer and their siblings, who served as controls, new-onset memory impairment emerged more often in survivors decades later.

The increased risk was associated with the cancer treatment that was provided as well as modifiable health behaviors and chronic health conditions.

Even 35 years after being diagnosed, cancer survivors who never received chemotherapies or radiation therapies known to damage the brain reported far greater memory impairment than did their siblings, first author Nicholas Phillips, MD, told this news organization.

What the findings suggest is that “we need to educate oncologists and primary care providers on the risks our survivors face long after completion of therapy,” said Dr. Phillips, of the epidemiology and cancer control department at St. Jude Children’s Research Hospital, Memphis, Tenn.

The study was published online in JAMA Network Open.

Cancer survivors face an elevated risk for severe neurocognitive effects that can emerge 5-10 years following their diagnosis and treatment. However, it’s unclear whether new-onset neurocognitive problems can still develop a decade or more following diagnosis.

Over a long-term follow-up, Dr. Phillips and colleagues explored this question in 2,375 adult survivors of childhood cancer from the Childhood Cancer Survivor Study and 232 of their siblings.

Among the cancer cohort, 1,316 patients were survivors of acute lymphoblastic leukemia (ALL), 488 were survivors of central nervous system (CNS) tumors, and 571 had survived Hodgkin lymphoma.

The researchers determined the prevalence of new-onset neurocognitive impairment between baseline (23 years after diagnosis) and follow-up (35 years after diagnosis). New-onset neurocognitive impairment – present at follow-up but not at baseline – was defined as having a score in the worst 10% of the sibling cohort.

A higher proportion of survivors had new-onset memory impairment at follow-up compared with siblings. Specifically, about 8% of siblings had new-onset memory trouble, compared with 14% of ALL survivors treated with chemotherapy only, 26% of ALL survivors treated with cranial radiation, 35% of CNS tumor survivors, and 17% of Hodgkin lymphoma survivors.

New-onset memory impairment was associated with cranial radiation among CNS tumor survivors (relative risk [RR], 1.97) and alkylator chemotherapy at or above 8,000 mg/m² among survivors of ALL who were treated without cranial radiation (RR, 2.80). The authors also found that smoking, low educational attainment, and low physical activity were associated with an elevated risk for new-onset memory impairment.

Dr. Phillips noted that current guidelines emphasize the importance of short-term monitoring of a survivor’s neurocognitive status on the basis of that person’s chemotherapy and radiation exposures.

However, “our study suggests that all survivors, regardless of their therapy, should be screened regularly for new-onset neurocognitive problems. And this screening should be done regularly for decades after diagnosis,” he said in an interview.

Dr. Phillips also noted the importance of communicating lifestyle modifications, such as not smoking and maintaining an active lifestyle.

“We need to start early and use the power of repetition when communicating with our survivors and their families,” Dr. Phillips said. “When our families and survivors hear the word ‘exercise,’ they think of gym memberships, lifting weights, and running on treadmills. But what we really want our survivors to do is stay active.”

What this means is engaging for about 2.5 hours a week in a range of activities, such as ballet, basketball, volleyball, bicycling, or swimming.

“And if our kids want to quit after 3 months, let them know that this is okay. They just need to replace that activity with another activity,” said Dr. Phillips. “We want them to find a fun hobby that they will enjoy that will keep them active.”

The study was supported by the National Cancer Institute. Dr. Phillips has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Adult survivors of childhood cancer have an elevated risk of developing cognitive impairment years after their cancer diagnosis and treatment, new research shows.

Among more than 2,300 adult survivors of childhood cancer and their siblings, who served as controls, new-onset memory impairment emerged more often in survivors decades later.

The increased risk was associated with the cancer treatment that was provided as well as modifiable health behaviors and chronic health conditions.

Even 35 years after being diagnosed, cancer survivors who never received chemotherapies or radiation therapies known to damage the brain reported far greater memory impairment than did their siblings, first author Nicholas Phillips, MD, told this news organization.

What the findings suggest is that “we need to educate oncologists and primary care providers on the risks our survivors face long after completion of therapy,” said Dr. Phillips, of the epidemiology and cancer control department at St. Jude Children’s Research Hospital, Memphis, Tenn.

The study was published online in JAMA Network Open.

Cancer survivors face an elevated risk for severe neurocognitive effects that can emerge 5-10 years following their diagnosis and treatment. However, it’s unclear whether new-onset neurocognitive problems can still develop a decade or more following diagnosis.

Over a long-term follow-up, Dr. Phillips and colleagues explored this question in 2,375 adult survivors of childhood cancer from the Childhood Cancer Survivor Study and 232 of their siblings.

Among the cancer cohort, 1,316 patients were survivors of acute lymphoblastic leukemia (ALL), 488 were survivors of central nervous system (CNS) tumors, and 571 had survived Hodgkin lymphoma.

The researchers determined the prevalence of new-onset neurocognitive impairment between baseline (23 years after diagnosis) and follow-up (35 years after diagnosis). New-onset neurocognitive impairment – present at follow-up but not at baseline – was defined as having a score in the worst 10% of the sibling cohort.

A higher proportion of survivors had new-onset memory impairment at follow-up compared with siblings. Specifically, about 8% of siblings had new-onset memory trouble, compared with 14% of ALL survivors treated with chemotherapy only, 26% of ALL survivors treated with cranial radiation, 35% of CNS tumor survivors, and 17% of Hodgkin lymphoma survivors.

New-onset memory impairment was associated with cranial radiation among CNS tumor survivors (relative risk [RR], 1.97) and alkylator chemotherapy at or above 8,000 mg/m² among survivors of ALL who were treated without cranial radiation (RR, 2.80). The authors also found that smoking, low educational attainment, and low physical activity were associated with an elevated risk for new-onset memory impairment.

Dr. Phillips noted that current guidelines emphasize the importance of short-term monitoring of a survivor’s neurocognitive status on the basis of that person’s chemotherapy and radiation exposures.

However, “our study suggests that all survivors, regardless of their therapy, should be screened regularly for new-onset neurocognitive problems. And this screening should be done regularly for decades after diagnosis,” he said in an interview.

Dr. Phillips also noted the importance of communicating lifestyle modifications, such as not smoking and maintaining an active lifestyle.

“We need to start early and use the power of repetition when communicating with our survivors and their families,” Dr. Phillips said. “When our families and survivors hear the word ‘exercise,’ they think of gym memberships, lifting weights, and running on treadmills. But what we really want our survivors to do is stay active.”

What this means is engaging for about 2.5 hours a week in a range of activities, such as ballet, basketball, volleyball, bicycling, or swimming.

“And if our kids want to quit after 3 months, let them know that this is okay. They just need to replace that activity with another activity,” said Dr. Phillips. “We want them to find a fun hobby that they will enjoy that will keep them active.”

The study was supported by the National Cancer Institute. Dr. Phillips has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Second-generation antiandrogens (AAs) – abiraterone, apalutamide, darolutamide, and enzalutamide – are a cornerstone of modern prostate cancer treatment, improving outcomes and survival.

However, they carry a significant caveat, according to a new meta-analysis of 12 clinical trials with over 13,000 patients.

These drugs come with a substantial risk of cognitive problems and fatigue and increase the risk of falls by 87%, the authors reported.

These findings carry “important public health indications” because use of second-generation AAs, currently first-line treatment for advanced and castration-resistant prostate cancer, is expanding with new indications, meaning that the pool of men at risk for such problems is large and growing, the team wrote.

The take-home message is that the findings give men – and the physicians who counsel them – a fuller idea of what to expect when considering using the agents, the researchers comment. This information is key at a time when so much of prostate cancer treatment involves carefully weighing the risks and benefits, they added.

The study was published in JAMA Oncology. It was conducted by a team of researchers from the University of Texas MD Anderson Cancer Center, Houston, and was led by Malgorzata Nowakowska, a medical student at Baylor College of Medicine, Houston.

Two prostate cancer specialists agreed and gave an example to bring the point home in an accompanying editorial.

The risk-benefit ratio of adding a second-generation AA to treatment may be different for a patient who wants to stay alert and sharp to keep a complex job “versus someone whose primary goal is to see their young children graduate high school,” Alexandra Sokolova, MD, of the Oregon Health and Science University, Portland, and Julie Graff, MD, of the VA Portland (Ore.) Health Care System, wrote in their editorial.

The study fills a “critical gap” when it comes to counseling men about the drugs and will help guide discussions, they said.

The investigators said their study also highlights the need for additional research to identify who is most at risk for the side effects and the best way to prevent and treat them. “Interventions currently under investigation include donepezil, methylphenidate, low-fat diet, acupuncture, martial arts, and high-intensity exercise, among many others,” Ms. Nowakowska and colleagues noted.
 

Study details

The 12 trials in the meta-analysis, which compared second-generation AAs with placebo, were conducted from 2008 to 2021. These trials were multinational investigations that included patients with metastatic disease as well as those with nonmetastatic disease. The median age across the studies ranged from 67 to 74 years, and trial follow-up ranged from 3.9 to 48 months.

The rates of adverse cognitive effects and attention disorders and disturbances ranged from 2% to 8% among patients who received second-generation AAs versus 2%-3% among those who received placebo, a more than doubling of the risk of cognitive toxic effects (P = .002).

Fatigue of any grade was reported in 5%-45% of participants taking second-generation AAs versus 2%-42% of patients taking placebos, which translates to a 34% higher risk (P < .001).

The use of AAs was associated with an 87% increase in the risk of falls in comparison with placebo, regardless of severity. For falls of grade 3 or higher that required hospitalization or invasive treatment, the increase in risk with second-generation AAs was 72% (P = .05).

The findings were consistent for cognitive toxicity and fatigue in studies that included traditional hormone therapy in both the treatment and control arms. Increased age was associated with a greater risk of fatigue.

Study limits include the fact that it was not known how long patients were taking the drugs before they encountered problems. In addition, the findings were not broken down with respect to medication, so it’s unknown whether such problems are worse with some second-generation AAs than with others.

The editorialists noted that real-world patients tend to be older and sicker than patients in trials, so the risk of falls, fatigue, and cognition problems might be higher among everyday patients.

The study was funded by the National Institutes of Health and others. The investigators disclosed no relevant financial relationships. Dr. Sokolova has received personal fees from Lantheus and travel grants from AstraZeneca. Dr. Graff has received nonfinancial support from Janssen, Pfizer/Astellas, and Sanofi.

A version of this article first appeared on Medscape.com.

Second-generation antiandrogens (AAs) – abiraterone, apalutamide, darolutamide, and enzalutamide – are a cornerstone of modern prostate cancer treatment, improving outcomes and survival.

However, they carry a significant caveat, according to a new meta-analysis of 12 clinical trials with over 13,000 patients.

These drugs come with a substantial risk of cognitive problems and fatigue and increase the risk of falls by 87%, the authors reported.

These findings carry “important public health indications” because use of second-generation AAs, currently first-line treatment for advanced and castration-resistant prostate cancer, is expanding with new indications, meaning that the pool of men at risk for such problems is large and growing, the team wrote.

The take-home message is that the findings give men – and the physicians who counsel them – a fuller idea of what to expect when considering using the agents, the researchers comment. This information is key at a time when so much of prostate cancer treatment involves carefully weighing the risks and benefits, they added.

The study was published in JAMA Oncology. It was conducted by a team of researchers from the University of Texas MD Anderson Cancer Center, Houston, and was led by Malgorzata Nowakowska, a medical student at Baylor College of Medicine, Houston.

Two prostate cancer specialists agreed and gave an example to bring the point home in an accompanying editorial.

The risk-benefit ratio of adding a second-generation AA to treatment may be different for a patient who wants to stay alert and sharp to keep a complex job “versus someone whose primary goal is to see their young children graduate high school,” Alexandra Sokolova, MD, of the Oregon Health and Science University, Portland, and Julie Graff, MD, of the VA Portland (Ore.) Health Care System, wrote in their editorial.

The study fills a “critical gap” when it comes to counseling men about the drugs and will help guide discussions, they said.

The investigators said their study also highlights the need for additional research to identify who is most at risk for the side effects and the best way to prevent and treat them. “Interventions currently under investigation include donepezil, methylphenidate, low-fat diet, acupuncture, martial arts, and high-intensity exercise, among many others,” Ms. Nowakowska and colleagues noted.
 

Study details

The 12 trials in the meta-analysis, which compared second-generation AAs with placebo, were conducted from 2008 to 2021. These trials were multinational investigations that included patients with metastatic disease as well as those with nonmetastatic disease. The median age across the studies ranged from 67 to 74 years, and trial follow-up ranged from 3.9 to 48 months.

The rates of adverse cognitive effects and attention disorders and disturbances ranged from 2% to 8% among patients who received second-generation AAs versus 2%-3% among those who received placebo, a more than doubling of the risk of cognitive toxic effects (P = .002).

Fatigue of any grade was reported in 5%-45% of participants taking second-generation AAs versus 2%-42% of patients taking placebos, which translates to a 34% higher risk (P < .001).

The use of AAs was associated with an 87% increase in the risk of falls in comparison with placebo, regardless of severity. For falls of grade 3 or higher that required hospitalization or invasive treatment, the increase in risk with second-generation AAs was 72% (P = .05).

The findings were consistent for cognitive toxicity and fatigue in studies that included traditional hormone therapy in both the treatment and control arms. Increased age was associated with a greater risk of fatigue.

Study limits include the fact that it was not known how long patients were taking the drugs before they encountered problems. In addition, the findings were not broken down with respect to medication, so it’s unknown whether such problems are worse with some second-generation AAs than with others.

The editorialists noted that real-world patients tend to be older and sicker than patients in trials, so the risk of falls, fatigue, and cognition problems might be higher among everyday patients.

The study was funded by the National Institutes of Health and others. The investigators disclosed no relevant financial relationships. Dr. Sokolova has received personal fees from Lantheus and travel grants from AstraZeneca. Dr. Graff has received nonfinancial support from Janssen, Pfizer/Astellas, and Sanofi.

A version of this article first appeared on Medscape.com.

Second-generation antiandrogens (AAs) – abiraterone, apalutamide, darolutamide, and enzalutamide – are a cornerstone of modern prostate cancer treatment, improving outcomes and survival.

However, they carry a significant caveat, according to a new meta-analysis of 12 clinical trials with over 13,000 patients.

These drugs come with a substantial risk of cognitive problems and fatigue and increase the risk of falls by 87%, the authors reported.

These findings carry “important public health indications” because use of second-generation AAs, currently first-line treatment for advanced and castration-resistant prostate cancer, is expanding with new indications, meaning that the pool of men at risk for such problems is large and growing, the team wrote.

The take-home message is that the findings give men – and the physicians who counsel them – a fuller idea of what to expect when considering using the agents, the researchers comment. This information is key at a time when so much of prostate cancer treatment involves carefully weighing the risks and benefits, they added.

The study was published in JAMA Oncology. It was conducted by a team of researchers from the University of Texas MD Anderson Cancer Center, Houston, and was led by Malgorzata Nowakowska, a medical student at Baylor College of Medicine, Houston.

Two prostate cancer specialists agreed and gave an example to bring the point home in an accompanying editorial.

The risk-benefit ratio of adding a second-generation AA to treatment may be different for a patient who wants to stay alert and sharp to keep a complex job “versus someone whose primary goal is to see their young children graduate high school,” Alexandra Sokolova, MD, of the Oregon Health and Science University, Portland, and Julie Graff, MD, of the VA Portland (Ore.) Health Care System, wrote in their editorial.

The study fills a “critical gap” when it comes to counseling men about the drugs and will help guide discussions, they said.

The investigators said their study also highlights the need for additional research to identify who is most at risk for the side effects and the best way to prevent and treat them. “Interventions currently under investigation include donepezil, methylphenidate, low-fat diet, acupuncture, martial arts, and high-intensity exercise, among many others,” Ms. Nowakowska and colleagues noted.
 

Study details

The 12 trials in the meta-analysis, which compared second-generation AAs with placebo, were conducted from 2008 to 2021. These trials were multinational investigations that included patients with metastatic disease as well as those with nonmetastatic disease. The median age across the studies ranged from 67 to 74 years, and trial follow-up ranged from 3.9 to 48 months.

The rates of adverse cognitive effects and attention disorders and disturbances ranged from 2% to 8% among patients who received second-generation AAs versus 2%-3% among those who received placebo, a more than doubling of the risk of cognitive toxic effects (P = .002).

Fatigue of any grade was reported in 5%-45% of participants taking second-generation AAs versus 2%-42% of patients taking placebos, which translates to a 34% higher risk (P < .001).

The use of AAs was associated with an 87% increase in the risk of falls in comparison with placebo, regardless of severity. For falls of grade 3 or higher that required hospitalization or invasive treatment, the increase in risk with second-generation AAs was 72% (P = .05).

The findings were consistent for cognitive toxicity and fatigue in studies that included traditional hormone therapy in both the treatment and control arms. Increased age was associated with a greater risk of fatigue.

Study limits include the fact that it was not known how long patients were taking the drugs before they encountered problems. In addition, the findings were not broken down with respect to medication, so it’s unknown whether such problems are worse with some second-generation AAs than with others.

The editorialists noted that real-world patients tend to be older and sicker than patients in trials, so the risk of falls, fatigue, and cognition problems might be higher among everyday patients.

The study was funded by the National Institutes of Health and others. The investigators disclosed no relevant financial relationships. Dr. Sokolova has received personal fees from Lantheus and travel grants from AstraZeneca. Dr. Graff has received nonfinancial support from Janssen, Pfizer/Astellas, and Sanofi.

A version of this article first appeared on Medscape.com.

The CD19-directed chimeric antigen receptor (CAR) T-cell therapy lisocabtagene maraleucel (liso-cel, Bristol-Myers Squibb), showed efficacy in achieving complete responses among patients with relapsed or refractory chronic lymphocytic leukemia (r/r CLL) or small lymphocytic lymphoma (SLL), after treatment with a Bruton kinase inhibitor (BTKi) and BCL2 inhibitor.

The phase 1/2 TRANSCEND CLL 004 trial represents “the first pivotal multicenter trial to evaluate a CAR T-cell therapy in heavily pretreated patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma,” first author Tanya Siddiqi, MD, associate professor in the division of lymphoma, City of Hope National Medical Center, Duarte, Calif., said in a press statement in connection with her presentation at the annual meeting of the American Society of Clinical Oncology.

“The durable complete responses observed with liso-cel in the TRANSCEND CLL 004 trial are remarkable and represent a major step in bringing a personalized, T cell–based treatment approach delivered as a one-time infusion into clinical practice for a complex and historically incurable disease,” she said.

Real-world evidence shows that patients with CLL or SLL who have relapsed or are refractory to treatment with BTKi therapy can have progressively worse outcomes. Moreover, with few other treatment options, research shows that the median time from dual discontinuation of BTKi and venetoclax to subsequent treatment failure or death is just 5.6 months.

“We are seeing a subset of patients now who are progressing on BTK inhibitors and venetoclax, and there is a high, unmet medical need for new, more effective treatments in this patient population,” Dr. Siddiqi said.

With liso-cel showing efficacy in the treatment of large B-cell lymphoma and receiving approval from the Food and Drug Administration for the indication, the multicenter TRANSCEND CLL 004 trial was launched to investigate the therapy’s effects in r/r CLL/SLL.

In a safety set of 117 patients with r/r CLL or SLL who received at least two prior lines of therapy, including a BTKi, patients received a single target dose of either 50 (n=9) or 100 × 106 (n = 87) CAR-positive T cells.

The primary efficacy analysis set included 49 patients who were treated with the target dose of 100 x 10⁶ CAR-positive viable T cells of liso-cel.

With a median on-study follow-up of 21.1 months, the primary endpoint of a complete response (CR) and complete response was achieved among 18.4% (n = 9; P = .0006).

Among patients achieving a complete response, no disease progression or deaths were reported, with a median duration of response that was not reached.

The undetectable minimal residual disease (MRD) rate was 63.3% in blood and 59.2% in bone marrow, which was associated with progression-free survival.

The overall response rate was 42.9%, which was not statistically significant, and the median duration of an objective response was 35.3 months (95% confidence interval, 11.01 to not reached).

The median time to first response was 1.2 months, and the median time to first complete response was 3.0 months.

The results were consistent in the broader safety set of 117 patients, including those who were heavily pretreated with a median of five prior lines of therapy (range, 2-12) and high-risk disease, with a CR rate of 18.4%.

In terms of safety, no new safety signals were observed, and the treatment’s safety profile was manageable, the authors noted.

Cytokine release syndrome (CRS), common with CAR T-cell therapy, occurred in 85% of patients; however, most cases were low grade; 9% of cases were grade 3, and there were no grade 4 or 5 cases.

Neurologic events occurred among 45%, including grade 3 in 17.9% and grade 4 in 0.9%, with no cases of grade 5.

For treatment of the CRS, 69.2% of patients received tocilizumab and/or corticosteroids for the cases of CRS and neurological events.

Of 51 deaths that occurred while on the study, 43 occurred following liso-cel infusion, including 5 caused by treatment-emergent adverse events occurring within 90 days of liso-cel infusion.

One death was determined to be related to liso-cel, involving macrophage activation syndrome–hemophagocytic lymphohistiocytosis.

“The safety profile was manageable, with low rates of grade 3 or higher CRS and neurotoxicity,” Dr. Siddiqi said.

She noted that, as encouraging as the results are, work should continue regarding further improving survival for patients.

“We need to look at this population more closely to see how we can make it even better for them,” she said in her talk.

For instance, “do we need to add maintenance, or do we need to do something else with CAR T therapy? Because one shot of CAR T is buying them a lot of time – 6 or 12 months of progression-free survival, but maybe we can make it even better.”

Dr. Siddiqi noted that she has “a lot of patients” who received CAR T-cell therapy who have not progressed or relapsed after as long as 4 years.

“I also have some patients who did relapse at 3 or 3 and 1/2 years, but everybody is so thankful for having that time of several years without any treatment; without the need for continuous therapy or continuous doctors’ visits. It is actually priceless,” she said.
 

Largest data set to date

Commenting on the study, Jakub Svoboda, MD, agreed that the findings suggest an important role of liso-cel among the growing numbers of patients who progress despite standard therapies.

“This is an important study and the [results] are very relevant as there is a growing population of patients with CLL/SLL who stopped responding to both BTKi and venetoclax and have limited options,” Dr. Svoboda, a medical oncologist at Penn Medicine, and associate professor of medicine at the Hospital of the University of Pennsylvania, both in Philadelphia, said in an interview.

“Many of my CLL/SLL patients benefited from BTK inhibitors and venetoclax for years, but it is clear that these are not curative agents, and ultimately our patients need other effective therapeutic options,” he said. “We have seen reports of smaller single-site studies with different anti-CD19 CAR T-cell products used in CLL/SLL in the past, but this multisite study using liso-cel represents the largest data set in over 100 patients with median follow-up of 21 months.”

Liso-cel, like other CAR T-cell treatments – which are derived from patients’ own cells that are then reengineered and delivered via a one-time infusion – has a 4-1BB costimulatory domain. This has the effect of enhancing the expansion and persistence of the CAR T cells.

Significantly, the study establishes that CAR T-cell manufacturing in CLL/SLL patients is feasible on a large scale, “which is important, considering the unique T-lymphocyte biology in CLL/SLL,” Dr. Svoboda remarked.

In terms of efficacy, “I have been mostly impressed by the high degree of undetectable minimal residual disease and the duration of response in the cohort of patients who previously failed both BTKi and venetoclax,” he added. “While there are a few agents used or being developed for patients failing both BTKi and venetoclax, it appears that CAR T-cell therapy has the unique potential to achieve long-term remissions in a subset of these patients.”

Discussant Carolyn Owen, MD, an associate professor in the division of hematology and hematological malignancies, University of Calgary (Alta.), and hematologist at the Tom Baker Cancer Centre, also in Calgary, also expressed enthusiasm over the encouraging results.

“The results of this study are very exciting,” she said during her discussion in the session.

“What is really important is that, even though this may be a small proportion of all of the patients, if we start offering this therapy a little bit earlier, and don’t wait for people to become completely refractory, we could increase the proportion of patients who are [not relapsing].”

Furthermore, “what’s most groundbreaking about this study is that patients could indeed have a really durable remission,” Dr. Owen added. “Hopefully not relapsing even beyond this 20-month follow up, which we haven’t seen with any of our other therapies.”

The results were also published in The Lancet.

The study was sponsored by Juno Therapeutics. Dr. Siddiqi disclosed relationships with Acerta Pharma, Ascentage Pharma, AstraZeneca, BeiGene, Bristol-Myers Squibb/Sanofi, Celgene, Juno Therapeutics, Kite, Oncternal Therapeutics, Pharmacyclics, and TG Therapeutics. Dr. Svoboda reported ties with Bristol-Myers Squibb. Dr. Owen disclosed relationships with Janssen, AstraZeneca, Roche Canada, AbbVie, Novartis Canada Pharmaceuticals, BeiGene, Merck, Incyte, and Seagen.

The CD19-directed chimeric antigen receptor (CAR) T-cell therapy lisocabtagene maraleucel (liso-cel, Bristol-Myers Squibb), showed efficacy in achieving complete responses among patients with relapsed or refractory chronic lymphocytic leukemia (r/r CLL) or small lymphocytic lymphoma (SLL), after treatment with a Bruton kinase inhibitor (BTKi) and BCL2 inhibitor.

The phase 1/2 TRANSCEND CLL 004 trial represents “the first pivotal multicenter trial to evaluate a CAR T-cell therapy in heavily pretreated patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma,” first author Tanya Siddiqi, MD, associate professor in the division of lymphoma, City of Hope National Medical Center, Duarte, Calif., said in a press statement in connection with her presentation at the annual meeting of the American Society of Clinical Oncology.

“The durable complete responses observed with liso-cel in the TRANSCEND CLL 004 trial are remarkable and represent a major step in bringing a personalized, T cell–based treatment approach delivered as a one-time infusion into clinical practice for a complex and historically incurable disease,” she said.

Real-world evidence shows that patients with CLL or SLL who have relapsed or are refractory to treatment with BTKi therapy can have progressively worse outcomes. Moreover, with few other treatment options, research shows that the median time from dual discontinuation of BTKi and venetoclax to subsequent treatment failure or death is just 5.6 months.

“We are seeing a subset of patients now who are progressing on BTK inhibitors and venetoclax, and there is a high, unmet medical need for new, more effective treatments in this patient population,” Dr. Siddiqi said.

With liso-cel showing efficacy in the treatment of large B-cell lymphoma and receiving approval from the Food and Drug Administration for the indication, the multicenter TRANSCEND CLL 004 trial was launched to investigate the therapy’s effects in r/r CLL/SLL.

In a safety set of 117 patients with r/r CLL or SLL who received at least two prior lines of therapy, including a BTKi, patients received a single target dose of either 50 (n=9) or 100 × 106 (n = 87) CAR-positive T cells.

The primary efficacy analysis set included 49 patients who were treated with the target dose of 100 x 10⁶ CAR-positive viable T cells of liso-cel.

With a median on-study follow-up of 21.1 months, the primary endpoint of a complete response (CR) and complete response was achieved among 18.4% (n = 9; P = .0006).

Among patients achieving a complete response, no disease progression or deaths were reported, with a median duration of response that was not reached.

The undetectable minimal residual disease (MRD) rate was 63.3% in blood and 59.2% in bone marrow, which was associated with progression-free survival.

The overall response rate was 42.9%, which was not statistically significant, and the median duration of an objective response was 35.3 months (95% confidence interval, 11.01 to not reached).

The median time to first response was 1.2 months, and the median time to first complete response was 3.0 months.

The results were consistent in the broader safety set of 117 patients, including those who were heavily pretreated with a median of five prior lines of therapy (range, 2-12) and high-risk disease, with a CR rate of 18.4%.

In terms of safety, no new safety signals were observed, and the treatment’s safety profile was manageable, the authors noted.

Cytokine release syndrome (CRS), common with CAR T-cell therapy, occurred in 85% of patients; however, most cases were low grade; 9% of cases were grade 3, and there were no grade 4 or 5 cases.

Neurologic events occurred among 45%, including grade 3 in 17.9% and grade 4 in 0.9%, with no cases of grade 5.

For treatment of the CRS, 69.2% of patients received tocilizumab and/or corticosteroids for the cases of CRS and neurological events.

Of 51 deaths that occurred while on the study, 43 occurred following liso-cel infusion, including 5 caused by treatment-emergent adverse events occurring within 90 days of liso-cel infusion.

One death was determined to be related to liso-cel, involving macrophage activation syndrome–hemophagocytic lymphohistiocytosis.

“The safety profile was manageable, with low rates of grade 3 or higher CRS and neurotoxicity,” Dr. Siddiqi said.

She noted that, as encouraging as the results are, work should continue regarding further improving survival for patients.

“We need to look at this population more closely to see how we can make it even better for them,” she said in her talk.

For instance, “do we need to add maintenance, or do we need to do something else with CAR T therapy? Because one shot of CAR T is buying them a lot of time – 6 or 12 months of progression-free survival, but maybe we can make it even better.”

Dr. Siddiqi noted that she has “a lot of patients” who received CAR T-cell therapy who have not progressed or relapsed after as long as 4 years.

“I also have some patients who did relapse at 3 or 3 and 1/2 years, but everybody is so thankful for having that time of several years without any treatment; without the need for continuous therapy or continuous doctors’ visits. It is actually priceless,” she said.
 

Largest data set to date

Commenting on the study, Jakub Svoboda, MD, agreed that the findings suggest an important role of liso-cel among the growing numbers of patients who progress despite standard therapies.

“This is an important study and the [results] are very relevant as there is a growing population of patients with CLL/SLL who stopped responding to both BTKi and venetoclax and have limited options,” Dr. Svoboda, a medical oncologist at Penn Medicine, and associate professor of medicine at the Hospital of the University of Pennsylvania, both in Philadelphia, said in an interview.

“Many of my CLL/SLL patients benefited from BTK inhibitors and venetoclax for years, but it is clear that these are not curative agents, and ultimately our patients need other effective therapeutic options,” he said. “We have seen reports of smaller single-site studies with different anti-CD19 CAR T-cell products used in CLL/SLL in the past, but this multisite study using liso-cel represents the largest data set in over 100 patients with median follow-up of 21 months.”

Liso-cel, like other CAR T-cell treatments – which are derived from patients’ own cells that are then reengineered and delivered via a one-time infusion – has a 4-1BB costimulatory domain. This has the effect of enhancing the expansion and persistence of the CAR T cells.

Significantly, the study establishes that CAR T-cell manufacturing in CLL/SLL patients is feasible on a large scale, “which is important, considering the unique T-lymphocyte biology in CLL/SLL,” Dr. Svoboda remarked.

In terms of efficacy, “I have been mostly impressed by the high degree of undetectable minimal residual disease and the duration of response in the cohort of patients who previously failed both BTKi and venetoclax,” he added. “While there are a few agents used or being developed for patients failing both BTKi and venetoclax, it appears that CAR T-cell therapy has the unique potential to achieve long-term remissions in a subset of these patients.”

Discussant Carolyn Owen, MD, an associate professor in the division of hematology and hematological malignancies, University of Calgary (Alta.), and hematologist at the Tom Baker Cancer Centre, also in Calgary, also expressed enthusiasm over the encouraging results.

“The results of this study are very exciting,” she said during her discussion in the session.

“What is really important is that, even though this may be a small proportion of all of the patients, if we start offering this therapy a little bit earlier, and don’t wait for people to become completely refractory, we could increase the proportion of patients who are [not relapsing].”

Furthermore, “what’s most groundbreaking about this study is that patients could indeed have a really durable remission,” Dr. Owen added. “Hopefully not relapsing even beyond this 20-month follow up, which we haven’t seen with any of our other therapies.”

The results were also published in The Lancet.

The study was sponsored by Juno Therapeutics. Dr. Siddiqi disclosed relationships with Acerta Pharma, Ascentage Pharma, AstraZeneca, BeiGene, Bristol-Myers Squibb/Sanofi, Celgene, Juno Therapeutics, Kite, Oncternal Therapeutics, Pharmacyclics, and TG Therapeutics. Dr. Svoboda reported ties with Bristol-Myers Squibb. Dr. Owen disclosed relationships with Janssen, AstraZeneca, Roche Canada, AbbVie, Novartis Canada Pharmaceuticals, BeiGene, Merck, Incyte, and Seagen.

The CD19-directed chimeric antigen receptor (CAR) T-cell therapy lisocabtagene maraleucel (liso-cel, Bristol-Myers Squibb), showed efficacy in achieving complete responses among patients with relapsed or refractory chronic lymphocytic leukemia (r/r CLL) or small lymphocytic lymphoma (SLL), after treatment with a Bruton kinase inhibitor (BTKi) and BCL2 inhibitor.

The phase 1/2 TRANSCEND CLL 004 trial represents “the first pivotal multicenter trial to evaluate a CAR T-cell therapy in heavily pretreated patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma,” first author Tanya Siddiqi, MD, associate professor in the division of lymphoma, City of Hope National Medical Center, Duarte, Calif., said in a press statement in connection with her presentation at the annual meeting of the American Society of Clinical Oncology.

“The durable complete responses observed with liso-cel in the TRANSCEND CLL 004 trial are remarkable and represent a major step in bringing a personalized, T cell–based treatment approach delivered as a one-time infusion into clinical practice for a complex and historically incurable disease,” she said.

Real-world evidence shows that patients with CLL or SLL who have relapsed or are refractory to treatment with BTKi therapy can have progressively worse outcomes. Moreover, with few other treatment options, research shows that the median time from dual discontinuation of BTKi and venetoclax to subsequent treatment failure or death is just 5.6 months.

“We are seeing a subset of patients now who are progressing on BTK inhibitors and venetoclax, and there is a high, unmet medical need for new, more effective treatments in this patient population,” Dr. Siddiqi said.

With liso-cel showing efficacy in the treatment of large B-cell lymphoma and receiving approval from the Food and Drug Administration for the indication, the multicenter TRANSCEND CLL 004 trial was launched to investigate the therapy’s effects in r/r CLL/SLL.

In a safety set of 117 patients with r/r CLL or SLL who received at least two prior lines of therapy, including a BTKi, patients received a single target dose of either 50 (n=9) or 100 × 106 (n = 87) CAR-positive T cells.

The primary efficacy analysis set included 49 patients who were treated with the target dose of 100 x 10⁶ CAR-positive viable T cells of liso-cel.

With a median on-study follow-up of 21.1 months, the primary endpoint of a complete response (CR) and complete response was achieved among 18.4% (n = 9; P = .0006).

Among patients achieving a complete response, no disease progression or deaths were reported, with a median duration of response that was not reached.

The undetectable minimal residual disease (MRD) rate was 63.3% in blood and 59.2% in bone marrow, which was associated with progression-free survival.

The overall response rate was 42.9%, which was not statistically significant, and the median duration of an objective response was 35.3 months (95% confidence interval, 11.01 to not reached).

The median time to first response was 1.2 months, and the median time to first complete response was 3.0 months.

The results were consistent in the broader safety set of 117 patients, including those who were heavily pretreated with a median of five prior lines of therapy (range, 2-12) and high-risk disease, with a CR rate of 18.4%.

In terms of safety, no new safety signals were observed, and the treatment’s safety profile was manageable, the authors noted.

Cytokine release syndrome (CRS), common with CAR T-cell therapy, occurred in 85% of patients; however, most cases were low grade; 9% of cases were grade 3, and there were no grade 4 or 5 cases.

Neurologic events occurred among 45%, including grade 3 in 17.9% and grade 4 in 0.9%, with no cases of grade 5.

For treatment of the CRS, 69.2% of patients received tocilizumab and/or corticosteroids for the cases of CRS and neurological events.

Of 51 deaths that occurred while on the study, 43 occurred following liso-cel infusion, including 5 caused by treatment-emergent adverse events occurring within 90 days of liso-cel infusion.

One death was determined to be related to liso-cel, involving macrophage activation syndrome–hemophagocytic lymphohistiocytosis.

“The safety profile was manageable, with low rates of grade 3 or higher CRS and neurotoxicity,” Dr. Siddiqi said.

She noted that, as encouraging as the results are, work should continue regarding further improving survival for patients.

“We need to look at this population more closely to see how we can make it even better for them,” she said in her talk.

For instance, “do we need to add maintenance, or do we need to do something else with CAR T therapy? Because one shot of CAR T is buying them a lot of time – 6 or 12 months of progression-free survival, but maybe we can make it even better.”

Dr. Siddiqi noted that she has “a lot of patients” who received CAR T-cell therapy who have not progressed or relapsed after as long as 4 years.

“I also have some patients who did relapse at 3 or 3 and 1/2 years, but everybody is so thankful for having that time of several years without any treatment; without the need for continuous therapy or continuous doctors’ visits. It is actually priceless,” she said.
 

Largest data set to date

Commenting on the study, Jakub Svoboda, MD, agreed that the findings suggest an important role of liso-cel among the growing numbers of patients who progress despite standard therapies.

“This is an important study and the [results] are very relevant as there is a growing population of patients with CLL/SLL who stopped responding to both BTKi and venetoclax and have limited options,” Dr. Svoboda, a medical oncologist at Penn Medicine, and associate professor of medicine at the Hospital of the University of Pennsylvania, both in Philadelphia, said in an interview.

“Many of my CLL/SLL patients benefited from BTK inhibitors and venetoclax for years, but it is clear that these are not curative agents, and ultimately our patients need other effective therapeutic options,” he said. “We have seen reports of smaller single-site studies with different anti-CD19 CAR T-cell products used in CLL/SLL in the past, but this multisite study using liso-cel represents the largest data set in over 100 patients with median follow-up of 21 months.”

Liso-cel, like other CAR T-cell treatments – which are derived from patients’ own cells that are then reengineered and delivered via a one-time infusion – has a 4-1BB costimulatory domain. This has the effect of enhancing the expansion and persistence of the CAR T cells.

Significantly, the study establishes that CAR T-cell manufacturing in CLL/SLL patients is feasible on a large scale, “which is important, considering the unique T-lymphocyte biology in CLL/SLL,” Dr. Svoboda remarked.

In terms of efficacy, “I have been mostly impressed by the high degree of undetectable minimal residual disease and the duration of response in the cohort of patients who previously failed both BTKi and venetoclax,” he added. “While there are a few agents used or being developed for patients failing both BTKi and venetoclax, it appears that CAR T-cell therapy has the unique potential to achieve long-term remissions in a subset of these patients.”

Discussant Carolyn Owen, MD, an associate professor in the division of hematology and hematological malignancies, University of Calgary (Alta.), and hematologist at the Tom Baker Cancer Centre, also in Calgary, also expressed enthusiasm over the encouraging results.

“The results of this study are very exciting,” she said during her discussion in the session.

“What is really important is that, even though this may be a small proportion of all of the patients, if we start offering this therapy a little bit earlier, and don’t wait for people to become completely refractory, we could increase the proportion of patients who are [not relapsing].”

Furthermore, “what’s most groundbreaking about this study is that patients could indeed have a really durable remission,” Dr. Owen added. “Hopefully not relapsing even beyond this 20-month follow up, which we haven’t seen with any of our other therapies.”

The results were also published in The Lancet.

The study was sponsored by Juno Therapeutics. Dr. Siddiqi disclosed relationships with Acerta Pharma, Ascentage Pharma, AstraZeneca, BeiGene, Bristol-Myers Squibb/Sanofi, Celgene, Juno Therapeutics, Kite, Oncternal Therapeutics, Pharmacyclics, and TG Therapeutics. Dr. Svoboda reported ties with Bristol-Myers Squibb. Dr. Owen disclosed relationships with Janssen, AstraZeneca, Roche Canada, AbbVie, Novartis Canada Pharmaceuticals, BeiGene, Merck, Incyte, and Seagen.